2-aminoquinoline derivatives

ABSTRACT

This invention provides 2-aminoquinoline derivatives represented by a general formula [I] 
     
       
         
         
             
             
         
       
         
         
           
             [in which R 1  and R 2  either stand for lower alkyl, lower cycloalkyl, etc., or R 1  and R 2  together form an aliphatic nitrogen-containing heterocycle with the nitrogen atom to which they bind; R 3 , R 4 , R 5 , R 6  and R 7  stand for hydrogen, lower alkyl, etc.; R 8  stands for lower alkyl, lower alkyloxy, etc.; and n stands for an integer of 0-4]. The compounds act as melanin concentrating hormone receptor antagonist, and are useful as medicines for central nervous system disorders, cardiovascular disorders and metabolic disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/JP2004/007217, filed May 20, 2004, whichclaims priority under 35 U.S.C. §365(b) from Japanese patent applicationNo. JP2003-143398, filed May 21, 2003.

TECHNICAL FIELD

This invention relates to 2-aminoquinoline derivatives which are usefulin the field of medicines. Said compounds act as antagonists to melaninconcentrating hormone receptor, and are useful as preventing or treatingagents of various diseases of cardiovascular system, nervous system,metabolic systems, reproductive system, respiratory system, digestivesystem and the like.

BACKGROUND ART

Melanin concentrating hormone (hereafter abbreviated as “MCH”) is acyclic peptide hormone/neuro-peptide, which was for the first timeisolated by Kawauchi, et al. in 1983 from sermon hypophysis [Nature,Vol. 305, 321 (1983)]. The hormone is known to functionally antagonizeto melanin cell stimulating hormone in fishes, to cause concentration ofmelanin granules in melanophore and participate in body color change[International Review of Cytology, Vol. 126, 1(1991); Trends inEndocrinology and Metabolism, Vol. 5, 120 (1994)]. Also in mammals,MCH-containing neuron nerve cells are localized in the hypothalamuslateral field and uncertain zone, but their nerve fibers are projectingover a very wide scope in the brain [The Journal of ComparativeNeurology, Vol. 319, 218 (1992)], and MCH is considered to preside overvarious central functions in living bodies.

Hypothalamus lateral field is known of old as feeding center, andfurthermore, recently molecular biological and pharmacological knowledgesuggesting participation of MCH in controlling energetic homeostasis arebeing accumulated. That is, it has been reported that expression ofmRNA, which is a MCH precursor, was accelerated in brains of ob/obmouse, db/db mouse, A^(y)/a mouse, Zucker fatty rat or the like whichare model animals of hereditary obesity, or in brains of fasted mice[Nature, Vol. 380, 243 (1996); Diabetes, Vol. 47, 294 (1998);Biochemical and Biophysical Research Communications, Vol. 268, 88(2000); Molecular Brain Research, Vol. 92, 43 (2000)].

Acute ventricular administration of MCH to rats was observed to induceaccelerated feeding activity [Nature, Vol. 380, 243 (1996)] and chronicadministration invites obesity accompanied by polyphagy [Proceedings ofthe National Academy of Science of the United States of America, Vol.99, 3240, (2002)]. Moreover, MCH precursor gene-deficient mouse showsreduced food ingestion or rise in oxygen consumption per body weightcompared to wild type mice. Its low body weight due to decrease in bodyfat was observed [Nature, Vol. 396, 670 (1998)].

On the contrary, the transgenic mouse which expresses excessive MCHprecursor develops obesity accompanied by polyphagy and insulinresistance [The Journal of Clinical Investigation, Vol. 107, 379(2001)]. Consequently, it is suggested that MCH is an important factorfor developing obesity and participates in diseases induced by metabolicdisorder or respiratory diseases of which one of risk factors isobesity. Besides, MCH is known to participate also in anxiety-causingaction, epilepsy, memory, learning, diuretic action, excretory action ofsodium and potassium, oxytocin secreting action, reproduction andreproductive function [Peptides, Vol. 17, 171 (1996); Peptides, Vol. 18,1095 (1997), Peptides, Vol, 15, 757 (1994); Journal ofNeuroendocrinology, Vol. 8, 57 (1996); Critical Reviews in Neurobiology,Vol. 8, 221, (1994)].

MCH causes versatile pharmacological actions through MCH receptors whichare present mainly in the central nervous system. As receptors of MCH,at least two types of type 1 receptors (MCH-1R or SLC-1) and type 2receptors (MCH-2R or SLT) are known [Nature, Vol. 400, 261 (1999);Nature, Vol. 400, 265 (1999); Biochemical and Biophysical ResearchCommunications, Vol. 261, 622 (1999); Nature Cell Biology, Vol. 1, 267(1999); FEBS Letters, Vol. 457, 522 (1999); Biochemical and PhysicalResearch Communications, Vol. 283, 1013 (2001); The Journal ofBiological Chemistry, Vol. 276, 20125 (2001); Proceedings of theNational Academy of Sciences of the United States of America, Vol. 98,7564 (2001); Proceedings of the National Academy of Sciences of theUnited States of America, Vol. 98, 7576 (2001); The Journal ofBiological Chemistry, Vol. 276, 34664 (2001); and MolecularPharmacology, Vol. 60, 632 (2001)].

Of those, the pharmacological action observed on rodents is inducedmainly via MCH-1R [Genomics, Vol. 79, 785(2002)]. Because MCH-1Rgene-deficient mice chronically administered with MCH do not developpolyphagy or obesity, it is known that controlling of energy exchange byMCH is induced via MCH-1R. Furthermore, deficiency of MCH-LR promotesactivity amount of mouse [Proceedings of the National Academy ofSciences of the United States of America, Vol. 99, 3240 (2002)], and itsparticipation in central diseases accompanied by behavioral disorder,for example, attention-deficit hyperactivity disorder, schizophrenia andthe like also is strongly suggested [Molecular Medicine Today, Vol. 6,43 (2000); Trends in Neuroscience, Vol. 24, 527 (2001)].

It is also reported that autoantibody to MCH-1R is present in serum ofvitiligo vulgaris patient [The Journal of Clinical Investigation, Vol.109, 923 (2002)]. Furthermore, expression of MCH-1R in certain speciesof cancer cells was reported, and in vivo expression sites of MCH andMCH-1R also suggest their participation in cancer, sleep, vigil, drugdependence and digestive disorders [Biochemical and Biophysical ResearchCommunications, Vol. 289, 44 (2001); Neuroendocrinology, Vol. 61, 348(1995); Endocrinology, Vol. 137, 561 (1996); The Journal of ComparativeNeurology, Vol. 435, 26 (2001)].

Functions of MCH are expressed upon its binding to MCH receptors.Therefore, when its binding to MCH receptor is inhibited, expression ofMCH action can be inhibited. In consequence, substances which areantagonists to binding of MCH to its receptor are useful as preventingor treating agent of those various diseases in which MCH participates,for example, metabolic disorders represented by obesity, diabetes,hormone disorder, hyperlipidemia, gout, fatty liver, hepatitis andcirrhosis; cardiovascular disorders, represented by stenocardia, acuteor congestive heart failure, myocardial infarction, coronaryatherosclerosis, hypertension, renal diseases and electrolyteabnormality; central nervous system or peripheral nervous systemdisorders represented by bulimia, emotional disturbance, depression,anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficithyperactivity disorder, memory impairment, sleep disorders, cognitivefailure, dyskinesia, paresthesias, smell disorders, morphine tolerance,drug dependence and alcoholism; reproductive disorders represented byinfertility, preterm labor and sexual dysfunction; digestive disorders;respiratory disorders; cancer or pigmentation.

Concerning heretofore known melanin concentration hormone receptorantagonists, for example, International Publications WO 01/21577, WO02/06245, WO 02/02744 and WO 01/82925; and JP 2002-3370A containrelevant disclosures.

For instance, JP2002-3370A disclosed the following compounds:

However, according to its specification, the Ar moiety is a monocyclicaromatic ring and does not include quinoline ring which is a bicyclicaromatic ring conceived for the present invention. Furthermore, as themoiety corresponding to Ar1, phenylpyrimidine ring which ischaracteristic to the derivatives of the present invention is notdisclosed. Thus the compounds differ from the derivatives of the presentinvention in structure. Still in addition, it is by no means easy toconceive based on the specification adoption of bicyclic aromaticquinoline ring as the Ar and phenylpyrimidine skeletal structure as theAr1 moiety, in combination.

Also WO 01/82925 disclosed the following compounds:

However, in the compounds represented by the above formula, Y(C₁-C₆spacer) is present between Ar and amino group, and they differ from thecompounds of the present invention in structure.

The object of the present invention is to provide 2-aminoquinolinederivatives which have an action to inhibit binding of MCH to MCH-1R,and also to provide preventing or treating agents utilizing them, ofdiseases such as metabolic disorders represented by obesity, diabetes,hormone disorder, hyperlipidemia, gout, fatty liver, hepatitis andcirrhosis; cardiovascular disorders, represented by stenocardia, acuteor congestive heart failure, myocardial infarction, coronaryatherosclerosis, hypertension, renal diseases and electrolyteabnormality; central nervous system or peripheral nervous systemdisorders represented by bulimia, emotional disturbance, depression,anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficithyperactivity disorder, memory impairment, sleep disorders, cognitivefailure, dyskinesia, paresthesias, smell disorders, morphine tolerance,drug dependence and alcoholism; reproductive disorders represented byinfertility, preterm labor and sexual dysfunction; digestive disorders;respiratory disorders; cancer or pigmentation.

DISCLOSURE OF THE INVENTION

We have engaged in concentrative studies with the view to developcompounds which inhibit binding of MCH to MCH-1R, to discover that thosecompounds of quinoline skeletal structure having an amino group at the2-position, with a specific phenylpyrimidine group bound to the6-position via an amide group were novel substances, have MCH-1Rantagonistic action and excel in pharmacolinetics. Based on thisknowledge, the present invention is completed.

Accordingly, therefore, the present invention provides:

-   -   (1) 2-aminoquinoline derivatives represented by a general        formula [I]

-   -    [in which R¹ and R² each independently stands for a substituent        selected from the group consisting of    -   1) optionally hydroxyl- or halogen-substituted lower alkyl,    -   2) optionally R⁹-substituted 3 to 6-membered cycloalkyl, and    -   3) optionally R⁹-substituted 4 to 6-membered heterocycloalkyl,        or    -   4) R¹ and R² together form a 4 to 11-membered crosslinking,        non-crosslinking or spiro ring aliphatic nitrogen-containing        heterocycle, with the nitrogen atom to which they bind, one or        two optional hydrogen atoms in the aliphatic nitrogen-containing        heterocycle being optionally substituted with R⁹;    -   R³, R⁴, R⁶ and R⁷ each independently stands for a substituent        selected from the group consisting of        -   1) hydrogen,        -   2) hydroxyl,        -   3) halogen, and        -   4) optionally halogen-substituted lower alkyl;    -   R⁵ stands for        -   1) hydrogen, or        -   2) optionally halogen-substituted lower alkyl;    -   R⁸ stands for a substituent selected from the group consisting        of        -   1) halogen,        -   2) lower alkyl, and        -   3) lower alkyloxy;    -   R⁹ stands for a substituent selected from the group consisting        of hydroxyl, amino, mono-lower alkylamino, di-lower alkylamino,        optionally hydroxyl- or halogen-substituted lower alkyl, (lower        alkyloxycarbonyl)amino, lower alkyloxycarbonyl-(lower        alkyl)amino, lower alkylcarbonylamino, lower alkylcarbonyl(lower        alkyl)amino, mono-lower alkylcarbamoyl (lower alkyl)amino,        di-lower alkylcarbamoyl(lower alkyl)amino, lower        alkylsulfonylamino, lower alkylsulfonyl(lower alkyl)amino, oxo        and 2-oxopyrrolidinyl; and    -   n is 0, 1, 2, 3 or 4]        or their pharmaceutically acceptable salts.

The invention furthermore provides:

-   -   (2) melanin concentrating hormone receptor antagonists        containing the compounds described in (1) above as the active        ingredient;    -   (3) preventing or treating agents containing the compounds        described in (1) above as the active ingredient, of diseases        such as metabolic disorders represented by obesity, diabetes,        hormone disorder, hyperlipidemia, gout, fatty liver, hepatitis        and cirrhosis; cardiovascular disorders, represented by        stenocardia, acute or congestive heart failure, myocardial        infarction, coronary atherosclerosis, hypertension, renal        diseases and electrolyte abnormality; central nervous system or        peripheral nervous system disorders represented by bulimia,        emotional disturbance, depression, anxiety, epilepsy, delirium,        dementia, schizophrenia, attention-deficit hyperactivity        disorder, memory impairment, sleep disorders, cognitive failure,        dyskinesia, paresthesias, smell disorders, morphine tolerance,        drug dependence and alcoholism; reproductive disorders        represented by infertility, preterm labor and sexual        dysfunction; digestive disorders; respiratory disorders; cancer        or pigmentation.    -   (4) medical composition containing the compounds described        in (1) above or their pharmaceutically acceptable salts and        medically acceptable carriers;    -   (5) a process for preparing the compounds represented by the        general formula [I]

-   -    [in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and n have the same        significations as given in (1) above],        which comprises a step of subjecting a compound of a general        formula [II]

-   -   [in which R¹, R², R³, R⁴ and R⁵ have the same significations as        given in (1) above] and a compound of a general formula [III]

-   -    [in which R⁶, R⁷, R⁸ and n have the same significations as        given in (1) above] to an amidation reaction.

Hereinafter the codes and terms used in the present specification areexplained.

As “halogen”, fluorine, chlorine, bromine and iodine can be named.

“Lower alkyl” includes C₁-C₆ alkyl, i.e., C₁-C₆ straight chain alkyl andC₃-C₆ branched chain alkyl, specific examples being methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-1-methylpropyland the like.

“Lower cycloalkyl” includes C₃-C₆ cycloalkyl, specific examples beingcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Lower cycloalkyloxy” signifies those groups in which C₃-C₆ cycloalkylbinds to oxygen, specific examples being cyclopropyloxy, cyclobutyloxy,cyclopentyloxy and cyclohexyloxy.

“Lower heterocycloalkyl” signifies C₃-C₆ cycloalkyl group in whichoptional one or two carbon atoms are substituted with nitrogen, oxygenor sulfur, specific examples including azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl,morpholinyl, 1-thia-4-azacyclohexyl and the like.

“Oxo” signifies a group in which two substituent groups form carbonylgroup with the carbon atom to which they bind. For example, as to R⁵, itrefers to the case where two R⁵s and the carbon atom to which they bindform a carbonyl group.

“Optionally fluorine-substituted lower alkyl” includes lower alkyl andfluorine-substituted lower alkyl, specific examples being, besidesabove-named lower alkyl groups, fluoromethyl, difluoromethyl,trifluoromethyl, 1,2-difluoroethyl, and the like.

“Optionally halogen-substituted lower alkyl” includes lower alkyl andhalogen-substituted lower alkyl, specific examples being, besidesabove-named lower alkyl groups, fluoromethyl, difluoromethyl,trifluoromethyl, 1,2-difluoroethyl, chloromethyl, dichloromethyl,trichloromethyl, 1,2-dichloroethyl, and the like.

“Optionally fluorine-substituted lower alkyloxy” includes those group inwhich lower alkyl or fluorine-substituted lower alkyl binds to oxygen,specific examples being: as lower alkoxy, methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butyloxy, isobutoxy, tert-butoxy, n-pentyloxy and thelike; and as fluorine-substituted lower alkyloxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, 1,2-difluoroethoxy, and the like.

“Mono-lower alkylamino” is an amino in which one of its hydrogen atomsis substituted with a lower alkyl, specific examples being methylamino,ethylamino, n-propylamino, isopropyl amino, n-butylamino,sec-butylamino, tert-butylamino, and the like.

“Di-lower alkylamino” signifies an amino whose two hydrogen atoms aresubstituted with lower alkyl groups, specific examples beingdimethylamino, diethylamino, ethylmethylamino, di(n-propyl)amino,methylpropylamino, diisopropylamino, and the like.

“Lower alkyloxycarbonyl” signifies lower alkyloxy-substituted carbonyl,e.g., C₁-C₆ alkyloxycarbonyl, specific examples being methoxycarbonyl,ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl,n-butyloxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,n-pentyloxycarbonyl, and the like.

“Lower alkyloxycarbonylamino” is an amino to which loweralkyloxycarbonyl is bound, which includes C₁-C₆ alkyloxycarbonyl-amino,specific examples being methoxycarbonylamino, ethoxycarbonylamino,n-propyloxycarbonylamino, isopropyloxy-carbonylamino,n-butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino,n-pentyloxycarbonylamino, and the like.

“Lower alkyloxycarbonyl (lower alkyl)amino” is a mono-lower alkylaminowhose hydrogen on the nitrogen atom is substituted with a loweralkyloxycarbonyl, specific examples being methoxycarbonyl(methyl)amino,ethoxycarbonyl(methyl)amino, n-propyloxycarbonyl(methyl)amino, and thelike.

“Lower alkylcarbonyl” is a carbonyl to which lower alkyl is bound, e.g.C₁-C₆ alkylcarbonyl, specific examples being acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.

“Lower alkylcarbonylamino” is an amino to which lower alkylcarbonyl isbound, specific examples being acetamino, propionylamino,isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino and thelike.

“Lower alkylcarbonyl(lower alkyl)amino” is a lower alkylamino in whichthe hydrogen on its nitrogen atom is substituted with loweralkylcarbonyl, specific examples including methylcarbonyl(methyl)amino,ethylcarbonyl(methyl)amino, n-propylcarbonyl(methyl)amino, and the like.

“Lower alkylcarbonyloxy” is a group in which a lower alkylcarbonyl isbound to oxygen, specific examples including acetoxy, propionyloxy,valeryloxy, isovaleryloxy, pivaloyloxy, and the like.

“Mono-lower alkylcarbamoyl” is a carbamoyl one of whose hydrogen atomsis substituted with lower alkyl, specific examples includingmethylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl,n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.

“Di-lower alkylcarbamoyl” is a carbamoyl whose two hydrogen atoms aresubstituted with lower alkyl groups, specific examples includingdimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl,di(n-propyl)carbamoyl, methylpropylcarbamoyl, diisopropylcarbamoyl, andthe like.

“Mono-lower alkylcarbamoylamino” is an amino one of whose hydrogen atomsis substituted with mono-lower alkylcarbamoyl group, specific examplesincluding methylcarbamoylamino, ethylcarbamoyl-amino,n-propylcarbamoylamino, isopropylcarbamoylamino, n-butylcarbamoylamino,sec-butylcarbamoylamino, tert-butylcarbamoylamino, and the like.

“Di-lower alkylcarbamoylamino” is an amino one of whose hydrogen atomsis substituted with di-lower alkylcarbamoyl, specific examples includingdimethylcarbamoylamino, diethylcarbamoylamino,di(n-propyl)carbamoylamino, diisopropylcarbamoylamino,di(n-butyl)carbamoylamino, di(sec-butyl)carbamoylamino,di(tert-butyl)carbamoylamino, and the like.

“Mono-lower alkylcarbamoyl(lower alkyl)amino” is a lower alkylaminowhose hydrogen on the nitrogen atom is substituted with mono-loweralkylcarbamoyl, specific examples includingmonomethylcarbamoyl(methyl)amino, monoethylcarbamoyl(methyl)-amino,mono(n-propyl)carbamoyl(methyl)amino, and the like.

“Di-lower alkylcarbamoyl(lower alkyl)amino” is a lower alkylamino whoseone hydrogen atom on the nitrogen atom is substituted with di-loweralkylcarbamoyl, specific examples includingdimethylcarbamoyl(methyl)amino, diethylcarbamoyl(methyl)amino,di(n-propyl)carbamoyl(methyl)amino, and the like.

“Mono-lower alkylcarbamoyloxy” is a group in which a mono-loweralkylcarbamoyl is bound to oxygen, specific examples includingmethylcarbamoyloxy, ethylcarbamoyloxy, n-propylcarbamoyloxy,isopropylcarbamoyloxy, n-butylcarbamoyloxy, sec-butylcarbamoyloxy,tert-butylcarbamoyloxy, and the like.

“Di-lower alkylcarbamoyloxy” is a group in which di-lower alkylcarbamoylis bound to oxygen, specific examples including dimethylcarbamoyloxy,diethylcarbamoyloxy, ethylmethyl-carbamoyloxy, di(n-propyl)carbamoyloxy,methylpropylcarbamoyloxy, diisopropylcarbamoyloxy, and the like.

“Lower alkylsulfonyl” is a group in which lower alkyl is bound tosulfonyl, specific examples including methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, and the like.

“Lower alkylsulfonylamino” is an amino one of whose hydrogen atoms issubstituted with lower alkylsulfonyl, specific examples includingmethylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,isopropylsulfonylamino, n-butylsulfonylamino, sec-butylsulfonylamino,tert-butylsulfonylamino, and the like.

“Mono-lower alkylsulfamoyl” is a sulfamoyl one of whose hydrogen atomsis substituted with lower alkyl, specific examples includingmonomethylsulfamoyl, monoethylsulfamoyl, mono(n-propyl)sulfamoyl,monoisopropylsulfamoyl, mono(n-butyl)-sulfamoyl,mono(sec-butyl)sulfamoyl, mono(tert-butyl)sulfamoyl, and the like.

“Di-lower alkylsulfamoyl” is a sulfamoyl whose two hydrogen atoms aresubstituted with lower alkyl groups, specific examples includingdimethylsulfamoyl, diethylsulfamoyl, di(n-propyl)sulfamoyl,diisopropylsulfamoyl, di(n-butyl)sulfamoyl, di(sec-butyl)sulfamoyl,di(tert-butyl)sulfamoyl, and the like.

“Mono-lower alkylsulfamoylamino” is an amino one of whose hydrogen atomsis substituted with a lower alkylsulfamoyl, specific examples includingmonomethylsulfamoylamino, monoethylsulfamoylamino,mono(n-propyl)sulfamoylamino, monoisopropylsulfamoyl-amino,mono(n-butyl)sulfamoylamino, mono(sec-butyl)-sulfamoylamino,tert-butylsulfamoylamino, and the like.

“Di-lower alkylsulfamoylamino” is an amino one of whose hydrogen atomsis substituted with di-lower alkylsulfamoyl, specific examples includingdimethylsulfamoylamino, diethylsulfamoylamino,ethylmethylsulfamoylamino, di(n-propyl)sulfamoylamino,methylpropylsulfamoylamino, diisopropylsulfamoylamino, and the like.

“Mono-lower alkylsulfamoyl(lower alkyl)amino” is a “mono-loweralkylamino” whose hydrogen on the nitrogen atom is substituted withlower alkylsulfamoyl, specific examples includingmonomethylsulfamoyl(methyl)amino, monoethylsulfamoyl(methyl)-amino,mono(n-propyl)sulfamoyl(methyl)amino, and the like.

“Di-lower alkylsulfamoyl(lower alkyl)amino” is a “mono-lower alkylamino”whose hydrogen on the nitrogen atom is substituted with di-loweralkylsulfamoyl, specific examples includingdimethylsulfamoyl(methyl)amino, diethylsulfamoyl(methyl)amino,di(n-propyl)sulfamoyl(methyl)amino, and the like.

As “4 to 11-membered crosslinking, non-crosslinking or spiro ringaliphatic nitrogen-containing heterocycle”, for example, as crosslinkingaliphatic nitrogen-containing heterocycle,2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane,octahydropyrrolo[3.4-b] pyrrole, octahydropyrrolo[3.4-c]pyrrole,3-azabicyclo[3.1.0]hexane, decahydropyrrolo[3,4-d]azepine, and the likecan be named;

As non-crosslinking aliphatic nitrogen-containing heterocycle, azetidinering, pyrrolidine ring, piperidine ring, hexamethylenimine ring,heptamethylenimine ring, morpholine ring, and the like can be named; and

as spiro ring aliphatic nitrogen-containing heterocycle,2-azaspiro[4.4]nonane, 1-oxa-7-azaspiro[4.4]nonane,2-oxa-7-azaspiro[4.4]nonane, 1,7-diazaspiro[4.4]nonane,3-oxa-1,7-diazaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane,2,7-diazaspiro[3.5]nonane, 2-azaspiro[3.3]heptane,2-oxa-6-azaspiro[3.3]heptane, 2,8-diazaspiro[4.5]decane, and the likecan be named.

“Pharmaceutically acceptable salts” of the compounds which arerepresented by the general formula [I] signify those customarily usedsalts which are permissible to be used in medicines, specific examplesincluding acid addition salts at amino or acid addition salts atnitrogen-containing heterocycle.

As such acid addition salts, inorganic acid salts such as hydrochloride,sulfate, nitrate, phosphate, perchlorate and the like; organic acidsalts such as maleate, fumarate, tartarate, citrate, ascorbate,trifluoroacetate and the like; and sulfonic acid salts such asmethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, andthe like can be named.

Compounds Represented by the General Formula [I]

In the compounds represented by the general formula [I],

R¹ and R² each independently stands for a substituent selected from thegroup consisting of

1) optionally hydroxyl- or halogen-substituted lower alkyl,

2) optionally R⁹-substituted 3 to 6-membered cycloalkyl, and

3) optionally R⁹-substituted 4 to 6-membered heterocycloalkyl, or

4) R¹ and R² together form a 4 to 11-membered crosslinking,non-crosslinking or spiro ring aliphatic nitrogen-containig heterocycle,with the nitrogen atom to which they bind, one or two optional hydrogenatoms in the aliphatic nitrogen-containing heterocyclic being optionallysubstituted with R⁹.

Specific examples of R¹ or R² include methyl, ethyl, n-propyl,isopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, chloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2-chloroethyl, cyclobutyl, cyclopentyl, cyclohexyl,tetrahydrofuran-2-yl, pyrrolidin-3-yl, N-acetylpyrrolidin-3-yl,N-methoxycarbonylpyrrolidin-3-yl, N-isopropylcarbonylpyrrolidin-3-yl,N-methylsulfonylpyrrolidn-3-yl, and the like.

When R¹ and R² together form 4 to 11-membered crosslinking,non-crosslinking or spiro ring nitrogen-containing aliphaticheterocycle, specific examples of the ring include azetidine,pyrrolidine, piperidine, morpholine, 2-azaspiro[4.4]nonane,1-oxa-7-azaspiro[4.4]nonane, 2-oxa-7-azaspiro[4.4]nonane,1,7-diazaspiro[4.4]nonane, 3-oxa-1,7-diazaspiro[4.4]nonane,2,7-diazaspiro[4.4]nonane, 2,7-diazaspiro[3.5]nonane,decahydropyrrolo[3,4-d]azepine, 2-azaspiro[3.3]heptane,2-oxa-6-azaspiro[3.3]heptane, 2,5-diazabicyclo[2.2.1]heptane,octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3.2-b]pyrrole,3-azabicyclo[3.1.0]hexane, octahydropyrrolo[1.2-a]pyrazine,octahydropyrrolo[3,4-d]azepine, 2,8-diazaspiro[4.5]decane, and the like.

R⁹ stands for a substituent selected from the group consisting ofhydroxyl, amino, mono-lower alkylamino, di-lower alkylamino, optionallyhydroxyl- or halogen-substituted lower alkyl, loweralkylcarbonylcarbonylamino, lower alkylcarbonylcarbonyl(loweralkyl)amino, lower alkylcarbonylamino, lower alkylcarbonyl(loweralkyl)amino, mono-lower alkylcarbamoyl(lower alkyl)amino, di-loweralkylcarbamoyl(lower alkyl)amino, lower alkylsulfonylamino, loweralkylsulfonyl(lower alkyl)amino, and 2-oxopyrrolidinyl.

Examples of preferred R⁹ include methyl, ethyl, hydroxymethyl,hydroxyethyl, amino, t-butylcarbonylamino,t-butylcarbonyl(methyl)-amino, methylamino, ethylamino,isopropyl(methyl)amino, 1-methyl-1-aminoethyl, 1-methyl-1-hydroxyethyl,methylcarbonyl-(methyl)amino, methylcarbonyl(ethyl)amino,ethylcarbonyl(methyl)-amino, ethylcarbonyl(ethyl)amino,isopropylcarbonyl(methyl)amino, isopropylcarbonyl(ethyl)amino,methoxycarbonyl(methyl)amino, ethoxycarbonyl(methyl)amino,t-butyloxycarbonylamino, methylsulfonyl(methyl)amino,methylsulfonyl(ethyl)amino, ethylsulfonyl(methyl)amino,dimethylsulfamoyl(methyl)amino, dimethylcarbamoyl,dimethylcarbamoyl(methyl)amino, 2-oxopyrrolidinyl,2-oxo-oxazolidin-3-yl, and the like.

Preferred R¹ or R² include methyl, ethyl, n-propyl, isopropyl,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, tetrahydrofuran-2-yl,pyrrolidin-3-yl, N-acetylpyrrolidin-3-yl,N-methoxycarbonylpyrrolidin-3-yl, N-isopropylcarbonylpyrrolidin-3-yl,N-methylsulfonylpyrrolidin-3-yl, and the like.

As the aliphatic nitrogen-containing heterocycle formed by R¹ and R²together with the nitrogen atom to which they bind, preferably thosesubstituent groups represented by a formula (A)

-   -   [in which R^(a) either stands for R⁹ or two R^(a)s together form        —(CH₂)x-(NH)—(CH₂)-, optional hydrogen in the substituent group        may optionally be substituted with lower alkyl, lower        alkylcarbonyl or oxo, x and y each independently stands for 0,        1, 2, 3 or 4 while satisfying the range specified by 3≦x+y≦4,        and m stands for 0, 1 or 2] are recommended.

As R^(a), lower alkylcarbonyl(lower alkyl)amino, loweralkylsulfonyl(lower alkyl)amino, lower alkyloxycarbonyl(loweralkyl)amino, and di-lower alkylcarbamoyl(lower alkyl)amino arerecommended.

Where m=2, two R^(a)s are independent of each other, while they maytogether form a group selected from the following:

here R¹⁰ being, for example, lower alkyl, or lower alkylcarbonyl.

Preferred R^(a) includes methylcarbonyl(methyl)amino,ethylcarbonyl(methyl)amino, ethylcarbonyl(ethyl)amino,isopropylcarbonyl(methyl)amino, isopropylcarbonyl(ethyl)amino,methanesulfonyl(methyl)amino, ethanesulfonyl(methyl)amino,methoxycarbonyl(methyl)amino, ethoxycarbonyl(methyl)amino,2-pyrrolidinon-1-yl and the like. Preferred R¹⁰ includes methyl, ethyl,methylcarbonyl, ethylcarbonyl and the like.

As preferred combination of R¹ and R²,

-   -   R¹: lower alkyl, R²: optionally hydroxyl-substituted lower alkyl    -   R¹: lower alkyl, R²: tetrahydrofuranyl    -   R¹: lower alkyl, R²: optionally R⁹-substituted pyrrolidinyl        -   R¹: methyl, R²: isopropyl        -   R¹: methyl, R²: tetrahydrofuranyl        -   R¹: methyl, R²: N-acetylpyrrolidin-3-yl        -   R¹: methyl, R²: N-methylpyrrolidon-4-yl        -   R¹: methyl, R²: N-methylsulfonylpyrrolidin-3-yl            and the like are recommended.

As the preferred substituents represented by the formula (A),1-methyl-2-oxo-1,7-diazaspiro[4.4]nonan-7-yl,7-methyl-8-oxo-2,7-diazaspiro[4.4]nonan-2-yl,3-[acetyl(methyl)amino]pyrrolidin-1-yl,3-[propionyl(methyl)amino]pyrrolidin-1-yl,3-[isobutyryl(methyl)amino]pyrrolidin-1-yl,3-[methanesulfonyl(methyl)amino]pyrrolidin-1-yl,3-[methoxycarbonyl(methyl)amino]pyrrolidin-1-yl,3-{[(dimethylamino)carbonyl](methyl)amino}pyrrolidin-1-yl,6-acetyldecahydropyrrolo[3,4-d]azepin-2-yl,2-oxo[1.3′]bipyrrolidinyl-1′-yl, and the like are recommended.

Of the substituents represented by the formula (A), those particularlypreferred are the following:

R³, R⁴, R⁶ and R⁷ each independently stands for a substituent selectedfrom the group consisting of

-   -   1) hydrogen,    -   2) hydroxyl,    -   3) halogen, and    -   4) optionally halogen-substituted lower alkyl.

As R³, R⁴, R⁶ and R⁷, hydrogen, fluorine, or methyl are preferred, inparticular, the case wherein all of them are hydrogen atoms isrecommended.

R⁵ stands for hydrogen or optionally halogen-substituted lower alkyl,preferably hydrogen, methyl or ethyl.

As R⁸, where n is 2, 3, or 4, each of them independently stands for asubstituent selected from the group consisting of

-   -   1) halogen,    -   2) lower alkyl, and    -   3) lower alkyloxy,        preferred examples being fluorine, methyl, ethyl, methoxy, and        the like, in particular, fluorine or methoxy.

Preferred n is 0, 1, or 2.

Of the compounds represented by the general formula [I], particularlythose represented by a general formula [I-1]

-   -   [in which R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(a), m and n are same as        earlier defined] are recommended.

Those compounds represented by the general formula [I-1] exhibit potentMCH-1R antagonistic activity and excel in oral absorption andintracerebral transmigration. They also show high selectivity amongother receptors and have excellent effect as medicines.

As specific compounds represented by the general formula [I],

-   5-(4-fluorophenyl)-N-[2-(1-methyl-2-oxo-1,7-diazaspiro[4.4]nonan-7-yl)-6-quinolinyl]-2-pyrimidinecarboxamide,-   5-(4-fluorophenyl)-N-[2-(7-methyl-8-oxo-2,7-diazaspiro[4.4]-nonan-2-yl)-6-quinolinyl]-2-pyrimidinecarboxamide,-   N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,-   N-[2-(6-acetyldecahydropyrrolo[3,4-d]azepin-2-yl)-6-quinolinyl]-5-phenyl-2-pyrimidinecarboxamide,-   N-[2-[(3R)-3-[acetyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,-   5-phenyl-N-(2-[(3R)-3-[propionyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide,-   N-(2-[(3R)-3-[methanesulfonyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,-   N-(2-[(3R)-3-[methoxycarbonyl(methyl)amino-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,-   N-(2-[(3R)-3-[[(dimethylamino)carbonyl)](methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,-   N-(2-[isopropyl(methyl)amino]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,-   5-(4-fluorophenyl)-N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide,-   N-(2-[(3R)-3-[acetyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-(4-fluorophenyl)-2-pyrimidinecarboxamide,-   5-(4-fluorophenyl)-N-(2-[methyl(tetrahydro-3-furanyl)amino]-6-quinolinyl)-2-pyrimidinecarboxamide,-   5-(3-fluorophenyl)-N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide,    and the like are recommended.

As the compounds represented by the general formula [I], specificexamples are given in Table 1.

TABLE 1 Example Formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

Preparation Methods of the Compounds Represented by the General Formula[I]

Those compounds as represented by the general formula [I] can beprepared by, for example, suitably combining the following preparationprocesses.

Preparation Process 1

Reaction Scheme 1

-   -   [in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and n are same as        earlier defined].

That is, by amidating a compound represented by the general formula [II]and a compound represented by the general formula [III], a compound ofthe general formula [I] can be obtained.

The amidation can be conducted by per se known methods, for example, onecomprising reacting a compound represented by the general formula [II]with a compound represented by the general formula [III] in the presenceof a condensing agent, or one comprising activating carboxylic acidmoiety of a compound represented by the general formula [III] by aconventionally known means to convert it to a reactive derivative andthen amidating said derivative with a compound represented by a generalformula [II] (cf. “Fundamentals and Experiments of Peptide Synthesis”,Nobuo IZUMIYA, et al., Maruzen Publishing Co., 1983, for both of thesemethods).

1) Method of Amidation in the Presence of a Condensing Agent

A compound represented by the general formula [II] is amidated with acompound of the general formula [III] in the optional presence of, forexample, N-hydroxybenzotriazole (HoBt), using a condensing agent such as1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl) andthe like.

The use ratio of the compound of the general formula [III] is, forexample, in the range of 0.9-2.0 moles per mole of the compoundrepresented by the general formula [II], in particular, 1.0-1.5 molesbeing recommended.

Also as the use rate of the condensing agent, 1.0-2.0 moles, preferably1.0-1.5 moles, per mole of the compound represented by the generalformula [III]is recommended.

When HoBt is used, its exemplary use rate can range 0.9-2.0 moles,preferably 1.0-1.2 moles, per mole of the compound represented by thegeneral formula [II].

Furthermore, dimethylaminopyridine may be added to the reaction systemfor accelerating the reaction, at a use rate of, for example, 0.1-1.0mole, preferably 0.1-0.5 mole, per mole of the compound represented bythe general formula [II].

The amidation reaction is preferably conducted in an organic solvent,examples of suitable solvent including ethers such as 1,4-dioxane(“dioxane”), tetrahydrofuran (“THF”), diethyl ether and the like;aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzeneand the like; halogenated hydrocarbons such as dichloroethane,chloroform, dichloromethane, carbon tetrachloride and the like;pyridine, ethyl acetate, N,N-dimethylformamide (“DMF”),dimethylsulfoxide (“DMSO”) and the like.

The reaction temperature may range, for example, 0-80° C., preferably20-50° C., and the reaction time, 1-48 hours.

2) Method of Amidation Via Reactive Derivative

An object compound is obtained by converting a compound (carboxylicacid) represented by the general formula [III] to a “reactivederivative” by such methods as:

-   -   a) conversion to an acid chloride with a chlorinating agent such        as thionyl chloride, oxalyl chloride, phosphorus oxychloride or        the like (acid chloride method),    -   b) conversion to a mixed acid anhydride using isobutyl        chloroformate, methyl chloroformate or the like (mixed acid        anhydride method), or    -   c) conversion to active esters such as p-nitrophenyl ester,        N-hydroxysuccinimide ester or the like (active ester method)        and thereafter subjecting the resulting reactive derivative,        either as isolated or without isolation, to an amidation        reaction with a compound represented by the general formula        [II]. Preparation of such reactive derivatives, furthermore, can        be conducted following those methods described in, for example,        “Fundamentals and Experiments of Peptide Synthesis” (Nobuo        IZUMIYA, et al, Maruzen Publishing Co., 1983).

As the use rate of the reactive derivative, for example, a range of0.8-3.0 moles, preferably 1.1-1.3 moles, per mole of the compoundrepresented by the general formula [II] is recommended.

This reaction can be accelerated by conducting it in the presence of abasic catalyst. As examples of useful basic catalyst, alkali metalcarbonates such as lithium carbonate, sodium carbonate, potassiumcarbonate and the like; alkali metal hydrogencarbonates such as sodiumhydrogencarbonate, potassium hydrogencarbonate and the like; and organicbases such as triethylamine, diisopropylethylamine, tri-n-butylamine,1.5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene,pyridine, N,N-dimethylaminopyridine and the like can be named.

As use rate of the basic catalyst, for example, 0.1-2.0 moles,preferably 0.1-1.2 moles, per mole of the reactive derivative isrecommended.

As the reaction solvent, those named in the above can be used, and asthe reaction temperature, for example, −50-80° C., preferably 0-30° C.are recommended. Exemplary reaction time ranges about 30 minutes-24hours, while preferably 30 minutes-15 hours is recommended.

Also in the amidation reaction using the reactive derivative,dimethylaminopyridine may be used.

Upon extracting and purifying the solution mixture containing a compoundrepresented by the general formula [I] as obtained according to any ofthe above methods, the compound of the general formula [I] can beisolated.

Production Process 2

Production process 2 is a process for producing the compoundsrepresented by the general formula [II].

Reaction Scheme 2

-   -   [in which X stands for halogen, trifluoromethanesulfonyloxy and        the like; and R¹, R², R³, R⁴ and R⁵ are same as earlier defined]        Step 2-1:

Upon heating compound 1 and compound 2 at 20-200° C., preferably 50-150°C., for 10 minutes-48 hours, preferably an hour-24 hours, preferably inthe presence of an inert solvent, compound 3 is obtained. This reactionmay be conducted in a sealed tube.

Examples of the inert solvent include dioxane, THF, acetonitrile, DMF,DMSO, acetone and the like, among which dioxane, DMF and DMSO arerecommended.

As use rate of compound 3, for example, it can be in the range of 1-50moles per mole of compound 2, in particular, 1-10 moles beingrecommended.

Then preferably the compound 3 is isolated from the reaction mixturecontaining the compound 3 and purified by any means known per se, andsent to the next step. Here as the means for isolation and purification,for example, solvent extraction, recrystallization, columnchromatography, liquid chromatography, fractionating thin layerchromatography (preparative TLC) and the like can be named. These meansare also applicable in the steps hereafter explained.

Step 2-2

Nitro group of compound 3 is reduced to provide compound 4.

As the reduction method, for example, one as described in WO 02/40019can be used. Where R⁵ is hydrogen, the compound 4 corresponds to acompound represented by the general formula [II].

Step 2-3

This step is for obtaining a compound represented by the general formula[II], through 1) a step of introducing Boc group into amino group ofcompound 4 (t-butyloxycarbonylation), 2) a step of reacting theresulting compound with R⁵—X, in the presence of a base such as NaH, and3) a step of deprotecting the Boc group of the resulting compound. Allof these steps can be carried out by means heretofore known.

Furthermore, compound 1 can be prepared by a known method [Heterocycles,Vol. 48, 2637 (1998)] or a method similar thereto. On the other hand,commercially available compounds can be utilized as compound 2, whichmay also be prepared by those methods as described in Examples in thepresent specification.

Production Process 3

Production process 3 is for preparing compounds represented by thegeneral formula [III].

Reaction Scheme 3

-   -   [in which L stands for hydroxyl, lower alkyloxy or the like; X        stands for halogen, trifluoromethanesulfonyloxy or the like; and        R⁶, R⁷, R⁸ and n are same as earlier defined].

A compound represented by the general formula [III] can be obtained byreacting compound 5 with compound 6 in a solvent, in the presence ofpalladium catalyst and base. Concerning this reaction (Suzuki coupling),for example, those methods as described in Tetrahedron, Vol. 58, 9633(2002) can be referred to.

As the palladium catalyst, for example,tetrakis-(triphenylphosphine)palladium, palladium acetate,dichlorobis-(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like canbe named, and as the base, potassium carbonate, sodium carbonate,potassium phosphate and the like can be named.

As the solvent, alcohols such as t-butanol, ethanol and the like; etherssuch as THF, 1,2-dimethoxyethane (DME); aromatic hydrocarbons such asbenzene, toluene and the like; or mixed solvents of these arerecommended.

Use rate of compound 6 may range 0.9-2.0 moles, preferably 1.0-1.5moles, per mole of compound 5. As that of the palladium catalyst, it maybe, for example, 0.01-0.5 mole per mole of compound 5, and as that ofbase, 1-5 moles per mole of compound 5.

The reaction temperature can range from room temperature to 150° C., inparticular, 70-150° C. being recommended. The reaction time can rangenormally 1-24 hours.

As compound 5, commercially available chemicals can be used. Alsocommercially available compound 6 can be used or it may be prepared byknown method [e.g., cf. Journal of Chemical Society, 3129 (1953)].

In the foregoing Production processes, when such groups as amino,hydroxyl, carboxyl, oxo, carbonyl and the like which do not participatein the reaction are present in the reactant(s), they can be suitablyprotected with protective groups of amino, hydroxyl, carboxyl, oxo orcarbonyl, respectively, before carrying out a reaction of any ofProduction processes 1-3. After the reactions, the protective groups canbe removed.

As “amino-protective group”, aralkyl such as benzyl, p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydril, trityland the like; lower alkanoyl such as formyl, acetyl, propionyl, butyryl,pivaloyl and the like; benzoyl; arylalkanoyl such as phenylacetyl,phenoxyacetyl and the like; lower alkyloxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, tert-butoxycarbonyland the like; aralkyloxycarbonyl such as benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, fluorenylmethoxycarbonyland the like; lower alkylsilyl such as trimethylsilyl,tert-butyldimethylsilyl and the like; phthaloyl and the like can benamed. In particular, acetyl, pivaloyl, benzoyl, ethoxycarbonyl,tert-butoxycarbonyl and phthaloyl are recommended.

As “hydroxyl-protective group”, for example, lower alkyl such as methyl,ethyl, propyl, isopropyl, tert-butyl and the like; lower alkylsilyl suchas trimethylsilyl, tert-butyldimethylsilyl and the like; loweralkyloxymethyl such as methoxymethyl, 2-methoxyethoxy-methyl and thelike; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl such asbenzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, trityl and the like; and acyl such as formyl, acetyl andthe like can be named. In particular, methyl, methoxymethyl,tetrahydropyranyl, trityl, trimethylsilylethoxymethyl,tert-butyldimethylsilyl and acetyl are recommended.

As “carboxyl-protective group”, for example, lower alkyl such as methyl,ethyl, propyl, isopropyl, tert-butyl and the like; lower haloalkyl suchas 2,2,2-trichloroethyl and the like; lower alkenyl such as 2-propenyl;and aralkyl such as benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl,trityl and the like can be named. In particular, methyl, ethyl,tert-butyl, 2-propenyl, benzyl, p-methoxybenzyl and benzhydryl arerecommended.

Means for removing protective groups differ depending on kind of theprotective groups and stability of individual compounds represented bythe general formula [I]. For example, the removal is conducted followingthose methods described in literature [cf. Protective Groups in OrganicSynthesis, T. W. Greene, John Wiley & Sons Co., (1981)] or thoseanalogous thereto, by solvolysis using acid or base, i.e., a method ofhaving, for example, from 0.01 mole to a large molar excess of acid,preferably trifluoroacetic acid, formic acid, hydrochloric acid or thelike; or from equimolar to a large molar excess of base, preferablypotassium hydroxide, calcium hydroxide or the like, act on the objectcompound; chemical reduction using hydrogenated metal complex or bycatalytic reduction using palladium-on-carbon catalyst or Raney nickelcatalyst.

Compounds which are obtained by the foregoing methods can be easilyisolated and purified by heretofore known separation means. As suchmeans, for example, solvent extraction, recrystallization, columnchromatography, liquid chromatography, preparative chromatography andthe like can be named.

Compounds of the present invention may have stereoisomers or tautomerssuch as optical isomers, diastereo isomers, geometrical isomers or thelike, depending on the form of their substituents. All of thesestereoisomers, tautomers and their mixtures are encompassed by thecompounds of the present invention.

Pharmaceutical Compositions Containing the Compounds Represented by theGeneral Formula [I]

Those compounds of the present invention can be administered orally orparenterally, and when formulated into preparation forms adapted foradministration, can provide preventing or treating agents for metabolicdisorders represented by obesity, diabetes, hormone disorder,hyperlipidemia, gout, fatty liver, hepatitis and cirrhosis;cardiovascular disorders, represented by stenocardia, acute orcongestive heart failure, myocardial infarction, coronaryatherosclerosis, hypertension, renal diseases and electrolyteabnormality; central nervous system or peripheral nervous systemdisorders represented by bulimia, emotional disturbance, depression,anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficithyperactivity disorder, memory impairment, sleep disorders, cognitivefailure, dyskinesia, paresthesias, smell disorders, morphine tolerance,drug dependence and alcoholism; reproductive disorders represented byinfertility, preterm labor and sexual dysfunction; digestive disorders;respiratory disorders; cancer or pigmentation. In particular, they areuseful as preventing or treating agents for obesity.

In the occasions of clinical use of the compounds of the presentinvention, the compounds may be formulated into various forms ofpreparation with addition of pharmaceutically acceptable carriersaccording to the mode of administration, and thereafter administered. Ascarriers in such occasions, various additives heretofore known in thefield of medical preparations can be used, examples of which includegelatine, lactose, sucrose, titanium dioxide, starch, crystallinecellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, cornstarch, microcrystalline wax, white petrolatum, magnesium metasilicatealuminate, anhydrous calcium phosphate, citric acid, trisodium citrate,hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester,polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castoroil, polyvinylpyrrolidone, magnesium stearate, light silicic anhydride,talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol,polyalkylene glycol, cyclodextrin or hydroxypropylcyclodextrin and thelike.

As the preparation forms formulated as mixtures of these carriers andthe compounds of the present invention, for example, solid preparationssuch as tablet, capsule, granule, powder or supporsitory; and liquidpreparations such as syrup, elixir, or injection and the like can benamed, which can be prepared following heretofore known methods in thefield of medical preparations. Furthermore, liquid preparations may takesuch a form as to be dissolved or suspended in water or in othersuitable medium immediately before use. Particularly, injections can bedissolved or suspended in physiological saline solution or glucosesolution where necessary, and buffer or preservative may further beadded thereto.

Those preparations can contain the compounds of the present invention ata rate of 1.0-100% by weight, preferably 1.0-60% by weight, to the wholeof individual pharmaceutical preparation; and 0-99.0% by weight,preferably 40-99.0% by weight, of pharmaceutically acceptable carrier.These preparations may also contain therapeutically active othercompound(s), for example, treating agents for diabetes, hypertension,arterial sclerosis and the like.

In case of using the compounds of the present invention as preventing ortreating agents of said diseases or sicknesses, their dosages andadministration frequency differ depending on sex, age, body weight andseriousness of symptoms of individual patients and the kind and scope ofintended therapeutic effect. Whereas, generally for oral administration,it is preferred to administer 0.01-400 mg per day per adult patient, asa single dose or several divided doses. For parenteral administrationpreferably 0.002-100 mg is administered as a single does or severaldivided doses. Depending on symptoms, preventing administration ispermissible.

Combination Therapy

The compounds of the present invention can be used in combination withdrugs effective for hypertension, obesity-associated hypertension,hypertension-associated diseases, cardiac hypertrophy, left ventricularhypertrophy, metabolic disorder, obesity, obesity-associated diseasesand the like (hereafter referred to as “drug for combined use”). Suchdrugs can be administered simultaneously, separately or in succession,for prevention or treatment of above-named diseases. When a compound ofthe present invention is used simultaneously with one, two or more ofdrugs for combined use, they may be formulated into a medicalpreparation suited for single administration form. Whereas, foroccasions of combination therapy, a composition containing the compoundof the present invention and drug(s) for combined use may beadministered to the object of medication in different packages, eithersimultaneously, separately or successively. They may be administered attime interval(s).

Dose(s) of drug(s) for combined use are determinable followingclinically adopted dose(s), which can be suitably selected according toindividual object of medication, administration route, specific disease,combination of drugs, and the like. Form of administering drug(s) forcombined use is not critical but it is sufficient that the compound ofthe present invention is combined with selected drug(s) for combined useat the time of administration. As adoptable administration forms, forexample, 1) administration of single preparation obtained bysimultaneously formulating a compound of the present invention anddrug(s) for combined use, 2) simultaneous administration of two kinds ofpreparations obtained by separately formulating a compound of thepresent invention and drug(s) for combined use, via a sameadministration route, 3) administration at a certain time interval, viaa same administration route, of two kinds of preparations obtained byseparately formulating a compound of the present invention and drug(s)for combined use, 4) simultaneous administration of two kinds ofpreparations obtained by separately formulating a compound of thepresent invention and drug(s) for combined use, via differentadministration routes, and 5) administration of two kinds preparationsobtained by separately formulating the compound of the present inventionand drug(s) for combined use, different administration routes, at acertain time interval (e.g., administration by the order of the compoundof the present invention and then the drug(s) for combined use, or bythe reversed order) can be adopted. The blend ratio of a compound of thepresent invention and drug(s) for combined use can be suitably selected,according to individual object of medication, administration route,disease and the like.

As drugs for combined use which can be used in the present invention,for example, those for treating diabetes, hyperlipidemia, hypertension,obesity and the like can be named. Two or more of such drugs forcombined use may be combined at an adequate ratio and used.

As drug for treating diabetes, for example, 1) PPAR γ agonists such asglitazones [e.g., ciglitazone, darglitazone, englitazone, isoglitazone(MCC-555) and the like], pioglitazone, rosiglitazone, troglitazone,BRL49653, CLX-0921, 5-BTZD, GW-0207, LG-100641, LY-300512 and the like;2) biganides such as metformin, buformin, phenformin and the like; 3)protein tyrosine phosphatase-1B inhibitor; 4) sulfonylureas such asacetohexamide, chloropropamide, diabinese, glibenclamide, glipizide,glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide,tolazamide, tolbutamide and the like; 5) meglitinides such asrepaglinide, nateglinide and the like; 6) α-glucosidohydroxylaseinhibitors such as acarbose, adiposine, camiglibose, emiglitate,miglitol, voglibose, pradimicin-Q, salbostatin, CKD-711, MDL-25,673,MDL-73,945, MOR 14 and the like; 7) α-amylase inhibitors such astendamistat, trestatin, A1 3688 and the like; 8) insulin secretionpromoters such as linogliride, A-4166 and the like; 9) fatty acidoxidation repressors such as clomoxir, etomoxir and the like; 10) A2antagonists such as midaglizole, isoglidole, deriglidole, idozoxan,earoxan, fluparoxan and the like; 11) insulin or insulin mimetics suchas biota, LP-100, novarapid, insulin detemir, insulini lispro, insulinglargine, insulin zinc, Lys-Pro-insulin, GLP-1(73-7), GLP 1 amide (7-36)and the like; 12) non-thiazolidindione such as JT-501, farglitazar andthe like; and 13) PPARα/γdual agonists such as MK-0767, CLX-0940,GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90 and SB219994 and thelike; can be named.

As said treating agent for hyperlipidemia, for example, 1) cholic acidabsorbefacients such as cholestyramine, colesevelem, colestipol,dialkylaminoalkyl derivatives of crossdextran, Colestid™, LoCholest™,Ovestram™ and the like; 2) HMG-CoA reductase inhibitors such asatorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, rosuvastatin, simvastatin, ZD4522 and the like; 3) HMG-CoAsynthesis inhibitors; 4) cholesterol absorption inhibitors such assnatol ester, β-sitosterol, sterol gluoside, ezetimibe and the like; 5)acyl coenzyme A cholesterol acyl transferase inhibitors such asavasimibe, eflucimibe, KY-505, SMP-709 and the like; 6) CETP inhibitorssuch as JTT 705, torcetrapib, CP532632, BAY-63-2149, SC-591, SC-795 andthe like; 7) squalene synthesis inhibitors; 8) antioxidants such asprobucol; 9) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, ethofibrate, fenofibrate, gemcabene,gemfibrozil, GW-7647, BM-170744, LY-518674, fibric acid derivatives[e.g., Atromid™, Lopid™, Tricor™ and the like; 10) FXR receptorantagonists such as GW-4064, SR-103912 and the like; 11) LXR receptoragonists such as GW3965, T9013137, XTCO-179628 and the like; 12)lipoprotein synthesis inhibitors such as niacin; 13) renin-angiotensininhibitors; 14) microsome-triglyceride transport inhibitors; 15) cholicacid resorption inhibitors such as BARA 1453, SC435, PHA384640, S-435,AZD7706 and the like; 16) PPAR δ agonists such as GW501516, GW590735 andthe like; 17) triglyceride synthesis inhibitors; 18) MTTP inhibitorssuch as LAB687, CP346086 and the like; 19) low density lipoproteinreceptor inducer; 20) squalene epoxidase inhibitors; 21) thrombocyteagglutination inhibitors; and 22) 5-lipoxygenase-activating proteininhibitors; can be named.

As said treating agents for hypertension, for example, 1) diuretic suchas thiazide-type diuretic, e.g., chlorothialidon, chlorothiazide,dichlorophenamide, hydrofluorothiazide, indapamide, hydrochlorothiazideand the like; loop-type diuretic, e.g., bumetanide, ethacrynic acid,furosemide, torsemide and the like; sodium-type diuretic such asamiloride, triamterene and the like; and aldosterone antagonist-typediuretic, e.g., spironolactone, epirenone and the like; 2) β-adrenalineblockers such as acebutolol, atenolol, betaxolol, bevantolol,bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol,indenolol, metaproplol, nadolol, nebivolol, penbutolol, pindolol,propanolol, sotalol, tertatolol, tilisolol, timolol and the like; 3)calcium channel blockers such as amlodipine, aranidipine, azelnidipine,barnidipine, benidipine, hepridil, cinaldipine, clevidipine, diltiazem,efonidipine, felodipine, gallopamil, isradipine, lacidipine.lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine,nimodepine, nisoldipine nitrendipine, manidipine, pranidipine, verapamiland the like; 4) angiotensin alteration enzyme inhibitors such asbenazepril, captopril, cilazapril, delapril, enalapril, fosinopril,imidapril, losinopril, moexipril quinapril, quinaprilat, ramipril,perindopril, perindropril, quanipril, spirapril, tenocapril,trandolapril, zofenopril and the like; 5) neutral endopeptidaseinhibitors such as omapatrilat, cadoxatril, ecadotril, fosidotril,sampatrilat, AVE 7688, ER 4030 and the like; 6) endothelin antagonistssuch as tezosentan, A308165, YM62899 and the like; 7) vasodilators suchas hydrazine, clonidine, minoxidil, nicotinyl alcohol and the like; 8)angiotension II antagonists such as candesartan, eprosartan, irbesartan,losartan, pratosartan, tasosartan, telmisartan, valsartan, EXP-3137,FI6828K, RNH6270 and the like; 9) α/β adrenaline blockers such asnipradilol, arotinolol, amosulalol and the like; 10) α1 blockers such asterazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin,naftopidil, indoramin, WHIP164, XEN010 and the like; 11) α2 agonistssuch as lofexidine, tiamenidine, moxonidine, rilmenidine, guanobenz andthe like; and 12) aldosteron inhibitors can be named.

As said anti-obesity agents, for example, 1) 5HT (serotonin) transporterinhibitors such as paroxetine, fluoxetine, fenfluramine, fluvoxamine,sertraline, imipramine and the like; 2) norepinephrine transporterinhibitors such as GW320659, desipramine, talsupram, nomifensine and thelike; 3) cannabinoid 1 receptor 1 (CB-1) antagonist/inverse agonist suchas rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo),BAY-65-2520 (Bayer), SLV-319 (Sorbay) and those compounds disclosed inU.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820,5,292,736, 5,624,941, 6,028,084, WO96/33159, WO98/33765, WO98/43636,WO98/43635, WO01/09120, WO01/96330, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO01/58869, WO02/076949,WO01/64632, WO01/64633, WO01/64634, WO03/006007, WO03/007887 andEP-658546, and the like; 4) ghrelin antagonists such as those compoundsdisclosed in, e.g., WO01/87355 and WO02/08250; 5) histamine (H3)antagonist/inverse agonist such as thioperamide, 3-(1Himidazol-4-yl)propyl N-(pentenyl)carbonate, clobenpropit,iodophenpropit, imoproxifan, GT2395, A331440, compounds disclosed inWO02/15905, 0-[3-(1H-imidazo-4-yl)propanol] carbamate,piperazin-containing H3 receptor antagonist (Lazewska, D. et al.,Pharmazie, 56:927-32 (2001), benzophenone derivatives (Sasse, A. et al.,Arch. Pharm. (Weinheim) 334:45-52 (2001)) substituted N-phenylcarbamate(Reidemeister, S. et al., Pharmazie, 55:83-6(2000)), proxyphenederivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)) and thelike; 6)MCH-1R antagonists such as T-226296(Takeda), SNAP-7941(Synaptic)and other compounds disclosed in WO01/82925, WO01/87834, WO02/051809,WO02/06245, WO02/076929, WO02/076947, WO02/04433, WO02/51809,WO02/083134, WO02/094799, WO03/004027 and JP2001-226269A, and the like;7) MCH-2R agonist/antagonists; 8) NPY1 antagonists such as3-chloro-5-(1-(6-[2-(5-ethyl-4-methyl-thiazol-2-yl)-ethyl]-4-morpholinyl-4-yl-pyridin-2-ylamino)-ethyl)phenyl]carbamic acid isopropyl ester, BIBP3226, BIB03304, LY-357897, CP-671906,GI-264879, and other compounds disclosed in USP6001836, WO96/14307,WO01/23387, WO99/51600, WO01/85690, WO01/85098, WO01/85173 andWO01/89528, and the like; 9) NPY5 antagonists such as L-152804,GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR235,208, FR226928,FR240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, LY366377,PD-160170, SR-120562A, SR-120819A, JCF-104, H409/22, and other compoundsdisclosed in U.S. Pat. Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298,6,337,332, 6,329,395, 340,683, 6,326,375, 6,329,395, 6,337,332,6,335,345, EP-01010691, EP-01044970, WO97/19682, WO97/20820, WO97/20821,WO97/20822, WO97/20823, WO98/27063, WO00/107409, WO00/185714,WO00/185730, WO00/64880, WO00/68197, WO00/69849, WO01/09120, WO01/14376,WO01/85714, WO1/85730, WO01/07409, WO01/02379, WO01/02379, WO01/23388,WO01/23389, WO01/44201, WO01/62737, WO01/62738, WO01/09120, WO02/20488,WO02/22592, WO02/48152, WO02/49648, WO02/094789 and Norman et al., J.Med. Chem. 43:4288-4312 (2000), and the like; 10) leptins such as humanrecombinant leptin (PEG-OB, Hoffman La Roche), recombinantmethionyl-leptin (Amgen) and the like; 11) leptin derivatives such asthose compounds which are disclosed in U.S. Pat. Nos. 5,552,524,5,552,523, 5,552,522, 5,521,283, WO96/23513, WO96/23514, WO96/23515,WO96/23516, WO96/23517, WO96/23518, WO96/23519 and WO96/23520, and thelike; 12) opioid antagonists such as Nalmefene (registered trademark toRevex), 3-methoxynaltrexone, naloxone, naltrexone, compounds disclosedin WO00/21509 and the like; 13) orexin antagonists such as SB-334867Aand other compounds disclosed in WO01/96302, WO01/68609, WO02/51232,WO02/51838, WO03/023561, and the like; 14) bombesin receptor subtype 3agonist; 15) cholecystolinin A (CCK-A) agonists such as AR-R15849,GI-181771, JMV-180, A-71378, A-71623, SR-146131, other compoundsdisclosed in USP-5739106, and the like; 16) CNTF (ciliary neurotrophicfactors) such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, PD149164 (Pfizer) and the like; 17)CNTF derivatives such as axokine (Regeneron), other compounds which aredisclosed in WO94/09134, WO98/22128 and WO99/43813, and the like; 18)growth hormone secretion receptor agonists such as NN 703, hexarelin,MK-0677, SM-130686, CP-424,391, L-692,429, L-163,255, U.S. Pat. No.6,358,951,U.S. Patent Application Nos. 2002/049196 and 2002/022637,WO01/56592 and WO02/32888, and the like; 19) serotonin receptor 2Cagonists such as BVT933, DPCA37215, IK264, PNU22394, WAY161503, R-1065,YM348, other compounds disclosed in U.S. Pat. No. 3,914,250, WO02/36596,WO02/48124, WO02/10169, WO01/66548, WO02/44152, WO02/51844, WO02/40456and WO02/40457, and the like; 20) melanocortin 3 receptor agonist; 21)melanocortin 4 receptor agonists such as CHIR86036 (Chiron), ME-10142,ME-10145 (Melacure), other compounds disclosed in WO99/64002,WO00/74679, WO01/991752, WO01/74844, WO01/70708, WO01/70337, WO01/91752,WO02/059095, WO02/059107, WO02/059108, WO02/059117, WO02/12166,WO02/11715, WO02/12178, WO02/15909, WO02/068387, WO02/068388,WO02/067869, WO03/007949 and WO03/009847, and the like; 22) monoamineresorption inhibitors such as Sibutramine (registered trademark toMeridia/Reductil) and salts thereof, other derivatives disclosed in U.S.Pat. Nos. 4,746,680 4,806,570, 5,436,272, US Patent Application No.2002/0006964, WO01/27068 and WO01/62341, and the like; 23) monoaminere-introjection inhibitors such as dexfenfluramine, fluoxetine, othercompounds disclosed in U.S. Pat. No. 6,365,633, WO01/27060 andWO01/162341, and the like; 24) glucagons-like peptide 1 agonist; 25)Topiramate (registered trademark to Topimax); 26) phytopharm compound 57(e.g., CP644,673); 27)acetyl CoA carboxylase 2 (ACC2) inhibitor; 28)β-adrenalin receptor 3 agonists such as AD9677/TAK677(DainipponPharmaceutical/Fakeda Pharmaceutical), CL-316,243, SB418790, BRL-37344,L-796568, BMS-196085, BRL-35135A, CGPI2177A, BTA-243, W427353,Trecadrine, ZenecaD7114, SR59119A, other compounds disclosed in U.S.Pat. Nos. 5,705,515, 5,451,677, WO01/74782 and WO02/32897, and the like;29) diacylglycerolacyl transferase 1 inhibitor; 30) diacylglycerolacyltransferase 2 inhibitor; 31) fatty acid synthesis inhibitors such asCerulenin, C75 and the like; 32) phosphodiesterase inhibitors such astheofylline pentoxyfylline, zaprinast, sildenafil, amrinone, milrinone,cilostamide, rolipram, cilomilast and the like; 32) thyroid hormone Pagonists such as KB-2611 (KaroBio BMS), other compounds disclosed inWO02/15845 and JP2000-256190A, and the like; 33) phytanic acid such asphytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid, other compounds disclosed inWO99/00123, and the like; 34) acyl estrogens such as oleoylestrone,compounds disclosed in del Mar-Grasa, M. et al., Obesity Reseach, 9:202-9 (2001); 35) glucocorticoid antagonist; 36) 11-β hydroxysteroiddehydrognase 1-type inhibitors such as BVT 3498, BVT 2733, othercompounds disclosed in WO01/90091, WO 01/90090 and WO01/90092, and thelike; 37) stearyl-CoA desaturase 1 inhibitors; 38) dipeptidyl peptidaseIV inhibitors such as isoleucine thiazolidide, valine pyrrolidide,NVP-DPP728 AF237, P93/01, TSL225, TMC-2A/2B/2C, FE999011, P9310/K364,VIP0177, SDZ274444, other compounds disclosed in WO03/004498,WO03/004496, EP1258476, WO02/083128, WO02/062764, WO03/000250,WO03/002530, WO03/002531, WO03/002553, WO03/002593, WO03/000180 andWO03/000181, and the like; 39) lipase inhibitors such as Tetrahydrolipstatin (registered trademark to Orlistat/Xenical), Triton WR 1339,RHC 80267, lipstatin, tea saponin, diethylumbelliferyl phosphate,FL-386, WAY-121898, BAY-N-3176, valilactone, esteracin, ebelactone A,ebelectone B, RHC80267, other compounds disclosed in WO01/77094, U.S.Pat. No. 4,598,089, U.S. Pat. No. 4,452,813, U.S. Pat. No. 5,512,565,U.S. Pat. No. 5,391,571, U.S. Pat. No. 5,602,151, U.S. Pat. No.4,405,644, U.S. Pat. No. 4,189,438 and U.S. Pat. No. 4,242,453, and thelike; 39) fatty acid transporter inhibitors; 40) dicarboxylatetransporter inhibitors; 41) glucose transporter inhibitors; 42)phosphate transporter inhibitors; and the like can be named.

Those combination drugs are obtained by concurrent use of a compound ofthe present invention with one, two, or more of above drugs for combineduse. Furthermore, said combination drugs are useful for prevention ortherapy of metabolic disorders, when combined with one, two or moredrugs selected from the group consisting of diabetes-treating agents andhyperlipidemia-treating agents. Combinations containing, in particular,hypertension-treating agent and antiobesity agent are useful forprevention or therapy of metabolic disorders with synergistic effect,when diabetes-treating agent(s) and/or hyperlipidemia-treating agent(s)are added thereto.

BRIEF EXPLANATION OF DRAWING

To rats satiated with high fat diet, compounds of the present inventionwere orally administered, and an hour after the administration, MCH wasintraventricularly administered. The rats' feed intakes during thefollowing two hours are shown in FIG. 1.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter the present invention is explained in detail referring toworking Examples, it being understood that the invention is in no senselimited by said Examples. Those reagents used in the Examples werecommercially available chemicals, unless otherwise specified. Massspectra were measured by Electro Spray Ionization Method (ESI).

REFERENTIAL EXAMPLE 1 1-Methyl-7-(6-nitro-2-quinolinyl)-2-oxo-1,7-diazaspiro[4,4]-nonane

(1) To a solution of diisopropylamine (12 ml) in THF (200 ml), n-butyllithium (2.6 M-hexane solution, 32 ml) was added under cooling with ice,followed by 20 minutes' stirring at the same temperature. The solutionwas then cooled to −78° C. and into which a THF solution (30 ml) of1-(tert-butyl)3-methyl 1,3-pyrrolidine-dicarboxylate (13.0 g) was addeddropwise, followed by an hour's stirring at the same temperature. Thenallyl bromide (10 ml) was added to the reaction liquid, followed by anhour's stirring at −78° C. and another hour's stirring at roomtemperature. Saturated aqueous ammonium chloride solution was added tothe reaction liquid which was subsequently extracted with ethyl acetate.The resulting ethyl acetate layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue wassubjected to column chromatography (hexane:ethyl acetate=15:1) toprovide 1-(tert-butyl)3-methyl 3-allyl-1,3-pyrrolidinedicarboxylate(13.3 g) as a yellow oily substance.

(2) To a THF-methanol (50 ml-50 ml) solution of the compound as obtainedin (1) (13.3 g, 40 mmol), 4N aqueous sodium hydroxide solution (20 ml)was added and stirred at 50° C. for an hour. The reaction liquid wasneutralized with 5N aqueous hydrochloric acid, extracted withchloroform, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The resulting residue was dissolved in toluene (100ml) and to which phenylphosphoryl-azide (13.5 g) and triethylamine (6.9ml) were added, followed by an hour's stirring at 80° C. Successivelybenzyl alcohol (6.6 ml) was added to the reaction liquid and stirred anovernight at 100° C. The reaction liquid was distilled under reducedpressure and the resulting residue was subjected to columnchromatography (hexane:ethyl acetate=6:1) to provide tertbutyl3-allyl-3-[(benzyloxy)carbonyl]-amino-1-pyrrolidinecarboxylate (13.0 g)as a colorless oily substance.

(3) To a THF (130 ml) solution of the compound as obtained in (2) (10.2g), 9-BBN (2M-THF solution, 113 ml) was added under cooling with ice,followed by an overnight stirring at room temperature. Further, methanol(2 ml), 3N aqueous sodium hydroxide solution (20 ml) and 30% aqueoushydrogen peroxide were added to the reaction liquid by the order stated,under cooling with ice followed by 3 hours' stirring at roomtemperature. Successively saturated aqueous sodium hydrogencarbonatesolution was added to the reaction liquid, followed by extraction withdiethyl ether. The diethyl ether layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The resulting residuewas subjected to column chromatography (hexane:ethyl acetate=3:2) toprovide tert-butyl3-[(benzyloxy)carbonyl]amino-3-(3-hydroxypropyl)-1-pyrrolidinecarboxylate(7.9 g) as a colorless oily substance.

(4) To a DMF (30 ml) solution of the compound as obtained in (3) (3.2g), imidazole (860 mg) and tert-butyldimethylchlorosilane (1.5 g) wereadded under cooling with ice, followed by 4 hours' stirring at roomtemperature. Water was added to the reaction liquid which was thenextracted with ethyl acetate, and the ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was dissolved in DMF (30 ml), and to the solution sodium hydride(60% oily substance, 500 mg) was added under cooling with ice, followedby an hour's stirring at the same temperature. Further methane iodide(1.3 ml) was added to the reaction liquid and stirred for 2 hours atroom temperature. The reaction liquid was poured into water, to whichsaturated aqueous ammonium chloride solution was added, followed byextraction with ethyl acetate. The ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. To theresidue tetrabutylammonium fluoride (1M-THF solution, 15 ml) was added,followed by an hour's stirring at room temperature. Saturated aqueousammonium chloride solution was further added to the reaction liquid,followed by extraction with ethyl acetate and the resulting ethylacetate layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was subjected to columnchromatography (hexane:ethyl acetate=3:2) to provide tert-butyl3-[[(benzyloxy)carbonyl](methyl)amino]-3-(3-hydroxypropyl)-1-pyrrolidinecarboxylate(3.4 g) as a colorless oily substance.

(5) A methylene chloride (100 ml) solution of oxalyl chloride (1.5 ml)was cooled to −78° C., to which DMSO (1.5 ml) was added, followed by 30minutes' stirring at the same temperature. Successively a methylenechloride (15 ml) solution of the compound as obtained in (4) (3.4 g) wasadded to the solution dropwise, followed by addition of triethylamine (7ml) and an hour's stirring at room temperature. Saturated aqueousammonium chloride solution was added to the reaction liquid, followed byextraction with ethyl acetate and the resulting ethyl acetate layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was dissolved in aqueous tert-butanol solution(75%, 200 ml), and to the solution 2-methyl-2-butene (4.5 ml), sodiumdihydrogenphosphate (2.0 g) and sodium chlorite (2.8 g) were added undercooling with ice, by the order stated, followed by an hour's stirring atroom temperature. Saturated aqueous ammonium chloride solution was addedto the reaction liquid, followed by extraction with ethyl acetate andthe resulting ethyl acetate layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue wasdissolved in methanol (30 ml), and to which solutiontrimethylsilyldiazomethane-hexane solution (2M-hexane solution, 20 ml)was added, followed by 30 minutes' stirring at room temperature. Afterdistilling the reaction liquid at reduced pressure, the residue wassubjected to column chromatography (hexane:ethyl acetate=5:1) to providetert-butyl3-([(benzyloxy)carbonyl](methyl)amino)-3-(3-methoxy-3-oxopropyl)-1-pyrrolidinecarboxylate(3.2 g) as a colorless oily substance.

(6) To a methanol (30 ml) solution of the compound as obtained in (5)(1.0 g), palladium hydroxide (200 mg) was added and stirred for 2 hoursat room temperature in hydrogen atmosphere. The reaction liquid wasfiltered, the solvent was distilled off under reduced pressure andtoluene (60 ml) was added to the resulting residue, followed by 2 hours'stirring at 100° C. Distilling the toluene off under reduced pressure,4N-hydrochloric acid-dioxane solution (20 ml) was added and stirred for2 hours at room temperature. Distilling the reaction liquid at reducedpressure, 2-chloro-6-nitroquinoline (620 mg), potassium carbonate (830mg) and isopropanol (20 ml) were added to the residue and the resultingmixture was stirred an overnight at 100° C. Water was added to thereaction liquid which then was extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was subjected to columnchromatography (ethyl acetate) to provide the title compound (740 mg) asa yellow solid. ESI-MS Found: m/z 327 [M+H]+

REFERENTIAL EXAMPLE 27-Methyl-2-(6-nitro-2-quinolinyl)-8-oxo-2,7-diazaspiro[4,4]-nonane

(1) A solution of 3-pyrrolidinol (4.0 g) in dioxane-water (10:1, 50 ml)mixed solvent was cooled to 5° C., and into which a solution of4-nitrobenzyl chloroformate (10.9 g) in dioxane (20 ml) was addeddropwise, while maintaining the pH at 8-9, followed by 10 minutes'stirring at 5° C. Distilling the solvent off under reduced pressure, theresidue was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, and from which the solvent wasdistilled off under reduced pressure. Washing the residue with ethylacetate, 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (6.6 g) wasobtained as a pale yellow solid.

(2) A solution of the compound as obtained in (1) (6.3 g) andtriethylamine (26.5 ml) in DMSO (76 ml) was cooled to 110° C., to whichpyridine sulfur trioxide complex (11.3 g) was added. After stirring thesystem an overnight at room temperature, water was added to the reactionliquid and extracted with dichloromethane. The organic layer was driedover anhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. Subjecting the resulting residue to silica gel columnchromatography (hexane:ethyl acetate=3:2-2:3),1-(p-nitrobenzyloxycarbonyl)-3-pyrrolidinone (4.5 g) was obtained.

1H-NMR(300 MHz,CDCl₃,δppm):2.65(2H,m), 3.88(4H,m), 5.24(2H,s),7.53(2H,d,J=7.5 Hz),8.22(2H,d,J=7.5 Hz).

(3) Sodium hydride (60% oily substance, 1.6 g) was suspended in THF (50ml) and cooled to 0° C. Into the suspension a solution of triethylphosphonoacetate (9.7 g) in THF (10 ml) was added dropwise, attemperatures not higher than 10° C., followed by 30 minutes' stirring at0-5° C. Into the reaction liquid a solution of the compound as obtainedin above (2) (3.5 g) in THF (10 ml) was added dropwise to 110° C. orbelow. After the following stirring for 4 hours at room temperature,water was added to the reaction liquid which was then distilled underreduced pressure. The residue was extracted with ethyl acetate andwashed with saturated saline. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. Subjecting the resulting residue to silica gel columnchromatography (hexane:ethyl acetate=4:1-3:2), p-nitrobenzyl3-(2-methoxy-2-oxoethyl)-3-(nitromethyl)-1-pyrrolidinecarboxylate (4.2g) was obtained.

1H-NMR(300 MHz,CDCl₃,δppm): 1.28(3H,t,J=7.5 Hz), 2.73(1H,m), 3.19(2H,m),3.65(1H,m), 4.14(2H,q,J=7.5 Hz), 4.21(2H,brs), 5.21(2H,s), 5.67(1H,m),7.52(2H,d,J=7.5 Hz), 8.22(2H,d,J=7.5 Hz).

(4) To a solution of the compound as obtained in (3) (3.9 g) innitromethane (160 ml), 1,1,3,3-tetramethylguanidine (0.8 ml) was addedand refluxed under heating an overnight. The reaction liquid wasconcentrated under reduced pressure, and the resulting residue wassubjected to silica gel column chromatography (hexane:ethylacetate=4:1-3:2) to provide p-nitrobenzyl3-(2-methoxy-2-oxoethyl)-3-(nitromethyl)-1-pyrrolidinecarboxylate (1.37g).

1H-NMR(300 MHz,CDCl₃,δppm): 1.28(3H,t,J=7.5 Hz), 2.04(2H,m), 2.63(2H,m),3.60(4H,m), 4.18(2H,q,J=7.5 Hz), 4.70(2H,m), 5.21(2H,s), 7.51(2H,d,J=7.5Hz), 8.22(2H,d,J=7.5 Hz).

(5) To a 50% aqueous methanol solution (80 ml) of the compound obtainedin (4) above (500 mg), iron powder (425 mg) and ammonium chloride (815mg) were added, and heated under reflux for 50 minutes. The reactionliquid was cooled to room temperature and filtered with Celite®. Thefiltrate was concentrated under reduced pressure, to which acetone (20ml) was added, and the supernatant was removed by decantation. DMF (20ml) was added to the residue and filtered through Celite®. Concentratingthe filtrate under reduced pressure, 3-oxo-2,7-diazaspiro[4,4]nonane wasobtained, which was used in the next step without purification.

(6) To a solution of the compound as obtained in (5) in DMF (10 ml),2-chloro-6-nitroquinoline (250 mg) and potassium carbonate (248 mg) wereadded, and stirred an overnight at 90° C. Distilling the solvent offunder reduced pressure, the resulting residue was subjected to silicagel column chromatography (chloroform:methanol=10:1) to provide2-(6-nitro-2-quinolinyl)-8-oxo-2,7-diazaspiro[4,4]-nonane (44 mg).1H-NMR(300 MHz,CDCl₃,δppm):2.17(1H,d,J=8.3 Hz), 2.21(1H,d,J=8.3 Hz),2.43(1H,d,J=15 Hz), 2.51(1H,d,J=15 Hz), 3.41(1H,d,J=11 Hz),3.47(1H,d,J=11 Hz), 3.73(4H,m), 6.82(1H,d,J=8.2 Hz), 7.68(1H,d,J=9.0Hz), 7.97(1H,d,J=9.0 Hz), 8.31(1H,dd,J=8.2,2.2 Hz), 8.55(1H,d,J=2.2 Hz).ESI-MS Found:m/z 313[M+H]+

(7) To a solution of the compound as obtained in (6) (44 mg) in DMF (4ml), sodium hydride (60% oily substance, 17 mg) was added under gaseousnitrogen stream, followed by 25 minutes' stirring at room temperature.To the reaction liquid a solution of methyl iodide (99 mg) in DMF (1 ml)was added and stirred for 30 minutes. Water was successively added tothe reaction liquid which then was extracted with chloroform-methanol(10:1) mixed solvent. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resulting residue was subjected to preparative TLC(chloroform:methanol=10:1) to provide the title compound (27 mg).

1H-NMR(300 MHz,CDCl₃,δppm):2.14(1H,d,J=8.3 Hz), 2.18(1H,d,J=8.3 Hz),2.49(1H,d,J=15 Hz), 2.56(1H,d,J=15 Hz), 2.81(3H,s), 3.39(1H,d,J=11 Hz),3.55(1H,d,J=11 Hz), 3.75(4H,m), 6.79(1H,d,J=8.2 Hz), 7.65(1H,d,J=9.0Hz), 7.95(1H,d,J=9.0 Hz), 8.28(1H,dd,J=8.2,2.2 Hz), 8.51(1H,d,J=2.2 Hz).ESI-MS Found:m/z 327[M+H]+

REFERENTIAL EXAMPLE 3(3R)-N-methyl-N-[1-(6-nitro-2-quinolinyl)-3-pyrrolidinyl]-isobutylamide

(1) To a solution of (3R)-(−)-1-benzyl-3-(methylamino)-pyrrolidine (20.0g) in tetrahydrofuran (200 ml), triethylamine (29.3 ml) anddi-tert-butyl-dicarbonate (34.4 g) were added at 0° C., followed bystirring an overnight at room temperature. Water was added to thereaction liquid which then was extracted with diethyl ether. The organiclayer was washed with saturated saline, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. To the residue 4Nhydrochloric acid-ethyl acetate solution (29.0 ml) was added, and formedwhite crystals were washed with diisopropyl ether, and filtered. Dryingthe product, tert-butyl(3R)-N-(1-benzyl-3-pyrrolidinyl)-N-methylcarbamate hydrochloride (24.2g) was obtained as white crystals. ESI-MS Found:m/z 235[M+H]+

(2) To a solution of the compound as obtained in above (1) (22.0 g) inmethanol (225 ml), 10% palladium-on-carbon (7.2 g) was added in gaseousnitrogen atmosphere, followed by an overnight stirring under oneatmospheric hydrogen atmosphere. The reaction was suspended bynitrogen-exchanging the reaction system, and the reaction liquid wasfiltered through Celite® and concentrated under reduced pressure. Dryingthe product, tert-butyl (3R)-N-methyl-N-(3-pyrrolidinyl)carbamatehydrochloride (15.9 g) was obtained as white crystals. ESI-MS Found:m/z201[M+H]+

(3) To a solution of 2-chloro-6-nitroaminoquinoline (7.13 g) in DMF (110ml), potassium carbonate (14.2 g) and the compound as obtained in above(2) (8.90 g) were added, and stirred an overnight at 90° C. To thereaction liquid water (400 ml) was added and the formed crystals wererecovered by filtration. The product was dried to provide tert-butyl(3R)-N-methyl-N-[1-(6-nitro-2-quinolinyl)-3-pyrrolidinyl]carbamate (11.4g) as yellow crystals. ESI-MS Found:m/z 273[M+H]+

(4) The compound as obtained in above (3) (11.2 g) was dissolved intrifluoroacetic acid (110 ml) and stirred for 20 minutes. The reactionliquid was concentrated under reduced pressure, and to the residue 2Naqueous sodium hydroxide solution was added, followed by extraction withchloroform. The organic layer was washed with saturated saline, driedover anhydrous sodium sulfate and concentrated under reduced pressure.To a solution of the resulting residue in chloroform (60 ml),triethylamine (8.4 ml) and isobutyryl chloride (3.8 ml) were added andstirred for an hour. Aqueous sodium hydrogencarbonate solution was addedto the reaction liquid which then was extracted with chloroforom. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography (chloroforom:methanol=95:5) to provide the title compound (10.3 g) as yellowcrystals. ESI-MS Found:m/z 243[M+H]+

REFERENTIAL EXAMPLE 42-(6-Nitro-2-quinolinyl)-6-acetyldecahydropyrrolo[3,4-d]-azepine

To a methanol (15 ml) solution of2-(t-butoxycarbonyl)-6-benzyldecahydropyrrolo[3,4-d]azepine (thiscompound had been prepared by the method as described in WO 99/40070)(680 mg), palladium-on-carbon (500 mg) was added and stirred undergaseous hydrogen stream (50 psi) an overnight at room temperature. Thepalladium-on-carbon was removed by filtration through Celite®, and thefiltrate was concentrated under reduced pressure. The resulting residuewas dissolved in chloroform (10 ml), to which triethylamine (516 mg) andacetyl chloride (200 mg) were added, followed by an hour's stirring atroom temperature. The reaction liquid was washed with saturated aqueoussodium carbonate solution, and the organic layer was dried overanhydrous magnesium sulfate. Distilling the solvent off under reducedpressure, the resulting residue was dissolved in trifluoroacetic acid (5ml) and stirred for 2 hours at room temperature. Distilling the solventoff under reduced pressure, the residue was dissolved in DMF (10 ml). Tothe solution 2-chloro-6-nitroquinoline (283 mg) and potassium carbonate(1.17 g) were added and stirred an overnight at 90° C. Distilling thesolvent off under reduced pressure and subjecting the resulting residueto silica gel column chromatography (chloroform:methanol=10:1), thetitle compound (424 mg) was obtained. ESI-MS Found:m/z 355[M+H]+

REFERENTIAL EXAMPLE 5(3R)-N-methyl-N-[1-(6-nitro-2-quinolinyl)-3-pyrrolidinyl]-acetamide

Referential Example 3 was repeated except that the isobutyryl chloridewhich was used in Referential example 3-(4) was replaced with acetylchloride, to provide the title compound.

1H-NMR(300 MHz,CDCl₃,δppm):2.05-2.40(5H,m), 2.85-3.05(3H,m),3.40-4.10(4H,m), 4.50-5.55(1H,m), 6.75-6.90(1H,m), 7.60-7.75(1H,m),7.90-8.05(1H,m), 8.20-8.40(1H,m),8.50-8.65(1H,m).

REFERENTIAL EXAMPLE 6(3R)-N-methyl-N-[1-(6-nitro-2-quinolinyl)-3-pyrrolidinyl]-propanamide

Referential Example 3 was repeated except that the isobutyryl chloridewhich was used in Referential example 3-(4) was replaced with propionylchloride, to provide the title compound.

1H-NMR(300 MHz,CDCl₃,δppm):1.10-1.30(3H,m), 2.10-2.60(4H,m), 2.85-3.05(3H,m), 3.40-4.10(4H,m), 4.50-5.55(1H,m), 6.75-6.90(1H,m),7.60-7.75(1H,m), 7.90-8.05(1H,m), 8.20-8.40(1H,m), 8.50-8.65(1H,m).

REFERENTIAL EXAMPLE 7(3R)-N-methyl-N-[1-(6-nitro-2-quinolinyl)-3-pyrrolidinyl]-methanesulfonamide

Referential Example 3 was repeated except that the isobutyryl chloridewhich was used in Referential example 3-(4) was replaced withmethanesulfonyl chloride, to provide the title compound.

1H-NMR(300 MHz,CDCl₃,δppm):2.15-2.45(2H,m), 2.85-3.00(3H,m),3.55-3.75(4H,m), 3.80-4.10(2H,m), 4.65-4.80(1H,m), 6.75-6.90(1H,m),7.60-7.75(1H,m), 7.90-8.05(1H,m), 8.20-8.35(1H,m), 8.50-8.60(1H,m).

REFERENTIAL EXAMPLE 8 2-[Isopropyl(methyl)amino]-6-nitroquinoline

Referential Example 2-(6) was repeated except that3-oxo-2,7-diazaspiro[4,4]nonane was replaced withN-isopropyl(methyl)amine, to provide the title compound. ESI-MSFound:m/z 246[M+H]+

REFERENTIAL EXAMPLE 9N-2-[methyl(tetrahydro-3-furanyl)amino]-6-nitroquinoline

Referential Example 2-(6) was repeated except that3-oxo-2,7-diazaspiro[4,4]nonane was replaced withN-methyl(tetrahydro-3-furanyl)amine, to provide the title compound.ESI-MS Found:m/z 274[M+H]+

REFERENTIAL EXAMPLE 10 5-Phenylpyrimidine-2-carboxylic acid

To a solution of 5-bromopyrimidine-2-carboxylic acid (5.01 g) andphenylboronic acid (3.61 g) in ethylene glycol dimethyl ether (150 ml),2M aqueous sodium carbonate solution (100 ml) andtetralcistriphenylphosphine palladium (1.42 g) were added and stirredfor 5 hours at 80° C. To the reaction liquid aqueous sodiumhydrogencarbonate solution was added, diluted with water and washed withdiethyl ether. To the aqueous layer 10% aqueous phosphoric acid wasadded to drop pH of the system to 4, followed by extraction with ethylacetate, washing with saturated saline, drying over anhydrous sodiumsulfate and concentration under reduced pressure. Thus the titlecompound (3.66 g) was obtained as white crystals. ESI-MS Found:m/z201[M+H]+ ESI-MS Found:m/z 199[M−H]−

REFERENTIAL EXAMPLE 11 5-(4-Fluorophenyl)pyrimidine-2-carboxylic acid

Referential Example 10 was repeated except that phenylboronic acid wasreplaced with 4-fluorophenylboronic acid, to provide the title compound.ESI-MS Found:m/z 219[M+H]+ ESI-MS Found:m/z 217[M−H]−

REFERENTIAL EXAMPLE 12 5-(3-Fluorophenyl)pyrimidine-2-carboxylic acid

Referential Example 10 was repeated except that phenylboronic acid wasreplaced with 3-fluorophenylboronic acid, to provide the title compound.ESI-MS Found: m/z 219[M+H]+ ESI-MS Found:m/z 217[M−H]−

EXAMPLE 15-(4-Fluorophenyl)-N-[2-(1-methyl-2-oxo-1,7-diazaspiro[4,4]-nonan-7-yl)-6-quinolinyl]-2-pyrimidinecarboxamide

To a methanol (5 ml) solution of the compound as obtained in ReferentialExample 1 (80 mg), palladium-on-carbon (10 mg) was added, and stirredfor an hour at room temperature in hydrogen atmosphere. The reactionliquid was filtered and the solvent was distilled off under reducedpressure. The residue was dissolved in chloroform (10 ml), to which thecompound as obtained in Referential Example 11 (53 mg), triethylamine(70 μl) and 2-chloro-1,3-dimethylimidazolium chloride (41 mg) wereadded. The resulting mixture was stirred an overnight at roomtemperature. Water was added to the reaction liquid which then wasextracted with ethyl acetate. The ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was subjected to column chromatography(chloroform:methanol=100:1) to provide the title compound (64 mg) as ayellow solid. 1H-NMR(400 MHz,CDCl₃,δppm):1.95-2.10(2H,m),2.13-2.24(1H,m), 2.36-2.55(3H,m), 2.87(3H,s), 3.60-3.78(3H,m),3.85-3.94(1H,m), 6.74(1H,d,J=9.2 Hz), 7.22-7.30(2H,m), 7.60-7.75(4H,m),7.96(1H,d,J=9.2 Hz), 9.07(2H,s), 10.01(1H,s).

EXAMPLE 25-(4-Fluorophenyl)-N-[2-(7-methyl-8-oxo-2,7-diazaspiro[4,4]-nonan-2-yl)-6-quinolinyl]-2-pyrimidinecarboxamidehydrochloride

Example 1 was repeated except that the compound as obtained inReferential Example 1 was replaced with that as obtained in ReferentialExample 2, and the resulting compound was treated with 4N-hydrochloricacid-ethyl acetate to provide the title compound. 1H-NMR(300MHz,d6-DMSO,δppm):2.15(2H,m), 2.44(2H,brs), 2.75(3H,s), 3.56(2H,m),3.85(4H,m), 7.27(1H,m), 7.45(2H,m), 8.01(2H,m),8.17(2H,m), 8.46(1H,m),8.62 (1H,brs), 9.36(2H, s), 11.18(1H, s). ESI-MS Found:m/z 497[M+H]+

EXAMPLE 3N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide

To a solution of the compound as obtained in Referential Example 3 (10.2g) in tetrahydrofuran (150 ml), 20% palladium hydroxide-on-carbon (4.19g) was added in nitrogen atmosphere, followed by an overnight's stirringin hydrogen atmosphere of one atmospheric pressure. The reaction systemwas nitrogen-exchanged to suspend the reaction, and the reaction liquidwas filtered with Celite®. The filtrate was concentrated under reducedpressure. To a solution of the residue in dimethylformamide (70 ml),phenylpyrimidinecarboxylic acid (5.97 g) as obtained in ReferentialExample 10 and triethylamine (8.3 ml) were added at 0° C., followed byfurther dropwise addition of a solution of2-chloro-1,3-dimethylimidazolium chloride (6.55 g) in dimethylformamide(30 ml) and subsequent an hour's stirring. After addition of aqueoussodium hydrogencarbonate solution to the reaction liquid and dilutionwith water, the formed solid was recovered by filtration. The solid wassubjected to silica gel column chromatography (chloroform:methanol=95:5)and recrystallized from ethyl acetate, to provide the title compound(7.65 g) as yellow crystals. 1H-NMR(400MHz,d6-DMSO,δppm):1.05-1.08(6H,m), 2.05-2.25(2H,m), 2.78(3/2H,s),2.96(3/2H,s), 2.82-3.10(1H,m), 3.35-3.55(2H,m), 3.65-3.87(2H,m),4.784.89(1/2H,m), 5.13-5.25(1/2H,m), 6.88-6.93(1H,m), 7.51-7.60(4H,m),7.90-7.92(3H,m), 8.01(1H,d,J=8.8 Hz), 8.36(1H,d,J=2.4 Hz), 9.34(2H,s),10.85(1H,s). ESI-MS Found:m/z 496[M+H]+

EXAMPLE 4N-[2-(6-acetyldecahydropyrrolo[3,4-d]azepin-2-yl)-6-quinolinyl]-5-phenyl-2-pyrimidinecarboxamide

Example 3 was repeated except that the compound as obtained inReferential Example 4 was used in place of that as obtained inReferential Example 3, to provide the title compound. 1H-NMR(300MHz,d6-DMSO,δppm):1.70-1.82(5H,m), 2.01(3H,s), 2.48 and 3.18(4H,m),3.32-3.67(5H,m), 6.84(1H,d,J=8.7 Hz), 7.54(4H,m), 7.91(3H,m),8.30(2H,m), 9.34(2H,s), 10.83(1H,s). ESI-MS Found:m/z 507[M+H]+

EXAMPLE 5N-(2-[(3R)-3-[acetyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide

Example 3 was repeated except that the compound as obtained inReferential Example 5 was used in place of that as obtained inReferential Example 3, to provide the title compound. 1H-NMR(300MHz,d6-DMSO,δppm):1.95-2.30(5H,m), 2.70-2.95(3H,m), 3.25-3.35(3H,m),3.35-3.60(2H,m), 3.60-3.90(2H,m), 4.60-5.25(1H,m), 6.85-6.95(1H,m),7.45-7.65(4H,m), 7.85-8.10(4H,m), 8.36(1H,s), 9.36(2H,s), 10.85(1H,s).ESI-MS Found:m/z 467[M+H]+

EXAMPLE 65-Phenyl-N-(2-[(3R)-3-[propionyl(methyl)amino]-1-pyrrolidnyl]-6-quinolinyl)-2-pyrimidinecarboxamide

Example 3 was repeated except that the compound as obtained inReferential Example 6 was used in place of that as obtained inReferential Example 3, to provide the title compound. 1H-NMR(300MHz,d6-DMSO,δppm):0.95-1.10(3H,m), 2.00-2.25(2H,m), 2.25-2.50(2H,m),2.70-2.95(3H,m), 3.35-3.60(2H,m), 3.60-3.85(2H,m), 4.65-5.30(1H,m),6.85-6.95(1H,m), 7.45-7.65(4H,m), 7.85-8.10(4H,m), 8.36(1H,s),9.36(2H,s), 10.84(1H,s). ESI-MS Found:m/z 481 [M+H]+

EXAMPLE 7N-(2-[(3R)-3-[methanesulfonyl(methyl)amino]-1-pyrroldinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide

Example 3 was repeated except that the compound as obtained inReferential Example 7 was used in place of that as obtained inReferential Example 3, to provide the title compound. 1H-NMR(300MHz,d6-DMSO,δppm):2.10-2.30(2H,m), 2.79(3H,s), 2.99(3H,s),3.40-3.60(2H,m), 3.70-3.90(2H,m), 4.454.60(1H,m), 6.85-6.95(1H,m),7.45-7.65(4H,m), 7.85-8.10(4H,m), 8.36(1H,s), 9.36(2H,s), 10.85(1H,s).ESI-MS Found:m/z 503[M+H]+

EXAMPLE 8N-(2-[(3R)-3-[methoxycarbonyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide(1)N-(2-[(3R)-3-[tert-butoxycarbonyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide

Example 3 was repeated except that tert-butyl(3R)-N-methyl-N-[1-(6-nitro-2-quinolinyl)-3-pyrrolidinyl]carbamate asobtained in Referential Example 3-(3) was used in place of the compoundas obtained in Referential Example 3, to provide the title compound.

(2)N-(2-[(3R)-3-[methoxycarbonyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide

The title compound was obtained by repeating Referential Example 3-(4)except that the compound as obtained in Referential Example 3-(3) wasreplaced with the compound as obtained in above (1) and isobutyrylchloride was replaced with methyl chlorocarbonate. 1H-NMR(400MHz,CDCl₃,δppm):2.18-2.27(2H,m), 2.90(3H,s), 3.53-3.61 (2H,m),3.75(3H,s),3.82-3.90(2H,m), 5.00(1H,br,s), 6.75(1H,d,J=9.2 Hz),7.52-7.59(3H,m), 7.65-7.74(4H,m), 7.94(1H,d,J=9.2 Hz), 8.43(1H,'s),9.12(2H,s), 10.04(1H,s). ESI-MS Found:m/z 483[M+H]+

EXAMPLE 9N-(2-[(3R)-3-[[(dimethylamino)carbonyl](methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide

The title compound was obtained by repeating Referential Example 3-(4)except that the compound as obtained in Referential Example 3-(3) wasreplaced with the compound as obtained in Example 8-(1) and isobutyrylchloride was replaced with dimethyl-carbamoyl chloride. 1H-NMR(400MHz,CDCl₃,δppm):1.59(6H,s), 2.12-2.21 (1H,m), 2.24-2.35(1H,m),2.82(3H,s), 3.49-3.62(2H,m), 3.82-3.90(1H,m), 3.92-4.00(1H,m),4.464.54(1H,m), 6.75(1H,d,J=9.2 Hz), 7.50-7.57(3H,m), 7.64-7.72(4H,m),7.92(1H,d,J=8.8 Hz), 8.40(1H,brs), 9.11(2H,s), 10.02(1H,s). ESI-MSFound:m/z 496[M+H]+

EXAMPLE 10N-(2-[isoropyl(methyl)amino]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide

The title compound was obtained by repeating Example 3, except that thecompound as obtained in Referential Example 3 was replaced with that asobtained in Referential Example 8. 1H-NMR(400MHz,CDCl₃,δppm):1.24(6H,d,J=6.8 Hz), 3.01 (3H,s),4.98(1H,septet,J=6.8Hz), 6.91(1H,d,J=9.2 Hz), 7.49-7.57(3H,m),7.62-7.69(4H,m), 7.89(1H,d,J=9.2 Hz), 8.38(1H,s), 9.10(2H,s),10.00(1H,s). ESI-MS Found:m/z 398[M+H]+

EXAMPLE 115-(4-Fluorophenyl)-N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide

Example 1 was repeated except that the compound as obtained inReferential Example 1 was replaced with the one as obtained inReferential Example 3. 1H-NMR(400 MHz,d6-DMSO,δppm):1.00-1.07(6H,m),2.06-2.25(2H,m), 2.77(3/2H,s), 2.82-2.91(1/2H,m), 2.96(3/2H,s),3.00-3.11(1/2H,m), 3.37-3.57(2H,m), 3.66-3.84(2H,m), 4.78-4.88(1/2H,m),5.12-5.23(1/2H,m), 6.88-6.94(1H,m), 7.40-7.44(2H,m), 7.54(1H,d,J=9.2Hz), 7.90(1H,dd,J=9.2,2.0 Hz), 7.96-8.02(3H,m), 8.34(1H,d,J=2.0 Hz),9.33(2H,s), 10.83(1H,s). ESI-MS Found:m/z 513[M+H]+

EXAMPLE 12N-(2-[(3R)-3-[acetyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-(4-fluorophenyl)-2-pyrimidinecarboxamide

Example 1 was repeated except that the compound as obtained inReferential Example 1 was replaced with the one as obtained inReferential Example 5. 1H-NMR(300 MHz,d6-DMSO,δppm): 1.95-2.25(5H,m),2.70-2.95(3H,m), 3.25-3.35(3H,m), 3.35-3.60(2H,m), 3.60-3.90(2H,m),4.60-5.30(1H,m), 6.85-6.95(1H,m), 7.35-7.60(3H,m), 7.85-8.10(4H,m),8.36(1H,s), 9.35(2H,s), 10.85(1H,s). ESI-MS Found: m/z 485[M+H]+

EXAMPLE 135-(4-Fluorophenyl)-N-(2-[methyl(tetrahydro-3-furanyl)amino]-6-quinolinyl)-2-pyrimidinecarboxamide

Example 1 was repeated except that the compound as obtained inReferential Example 1 was replaced with the one as obtained inReferential Example 9. 1H-NMR(400 MHz,CDCl₃,δppm):1.94-2.04(1H,m),2.32-2.42(1H,m), 3.10(3H,s), 3.75-3.96(3H,m), 4.08-4.15(1H,m),5.64-5.74(1H,m), 6.94(1H,d,J=9.2 Hz), 7.22-7.30(2H,m), 7.60-7.74(4H,m),7.94(1H,d,J=9.2 Hz), 8.41(1H,s), 9.06(2H,s), 10.00(1H,s). ESI-MSFound:m/z 444[M+H]+

EXAMPLE 145-(3-Fluorophenyl)-N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide

Example 3 was repeated except that 5-phenylpyrimidine-2-carboxylic acidwas replaced with the compound as obtained in Referential Example 12, toprovide the title compound. 1H-NMR(400MHz,d6-DMSO,δppm):1.01-1.07(6H,m), 2.07-2.25(2H,m), 2.77(3/2H,s),2.83-2.91(1/2H,m), 2.95(3/2H,s), 3.00-3.08(1/2H,m), 3.38-3.56(2H,m),3.66-3.85(2H,m), 4.78-4.88(1/2H,m), 5.12-5.23(1/2H,m), 6.89-6.94(1H,m),7.34-7.39(1H,m), 7.54(1H,d,J=8.8 Hz), 7.62(1H,dd,J=8.0,6.0 Hz),7.78(1H,d,J=8.0 Hz), 7.85(1H,dt,J=10.4,2.0 Hz), 7.90(1H,dd,J=9.2,2.0Hz), 8.01 (1H,d,J=8.8 Hz), 8.34(1H,d,J=2.0 Hz), 9.38(2H,s), 10.84(1H,s).ESI-MS Found:m/z 513[M+H]+

PHARMACOLOGICAL TEST EXAMPLES

Medical utility of compounds of the present invention is verified, forexample, by the following pharmacological test examples.

Pharmacological Test Example 1

MCH Binding Inhibition Test

A human MCH-1R encoding cDNA sequence [FEBS Letters, Vol. 398, p. 253(1996); Biochimica et Biophisica Acta, Vol. 1401, p. 216 (1998)] wascloned to plasmid vector pEF/mic/cyto (Invitrogen Corporation). Theobtained expression vector was transfected to a host cell CHO-K1(American Type Culture Collection) using lipofectamine plus reagent(Life Technology Inc.) to provide MCH-1R expression cells.

Membrane samples prepared from the MCH-1R expression cells wereincubated with each test compound and 50 pM of [¹²⁵I]MCH (NEN Co.), inan assay buffer (50 mM Tris buffer comprising 10 mM magnesium chloride,2 mM ethylenediamine tetraacetate, 0.01% bacitracin and 0.2% bovineserum albumin; pH 7.4) at 25° C. for an hour, followed by filtrationthrough Glass Filter GF/C (Wattman Co.). After washing the glass filterwith 50 mM Tris buffer (pH7.4) comprising 10 mM magnesium chloride, 2 mMethylenediamine tetraacetate and 0.04% Tween-20, radio activity on theglass filter was measured. Non-specific binding was measured in thepresence of 1 μM human MCH and 50% inhibition concentration (IC₅₀ value)of each test compound to specific [¹²⁵I] MCH binding was determined. Theresults were as shown in Table 2.

TABLE 2 Test Compound IC₅₀ (nM) Example 1 8.0 Example 3 4.1 Example 93.7

Test Example 2 Antagonism Test to MCH-Induced Feeding Behavior

Ketamine-xylazine anesthetized (74 and 11 mg/kg single intraperitonealadministration) male SD rats (9-12 weeks old) were inserted with chronicguide cannule (26 gauge) into their third ventricle as fixed at a setcerebral location with dental resin. The position of the front end ofthe guide cannula was set to be 2.2 mm behind the bregma on median lineand at a depth of 8 mm from the cranial surface. After two weeks'recovery term, the rats were fed with high fat diet for about 4 hours tosatiation. Thereafter a needle (33 gauge) which was connected to amicrosyringe was inserted into the guide cannula and through whichmelanin concentrating hormone (MCH, 5 μg/1 μL/head, as dissolved inartificial liquor cerebrospinalis) was administered into each rat'sthird ventricle. The compound of Example 3 (10 or 30 mg/kg) as suspendedin 0.5% aqueous methylcellulose solution was orally administered to therats an hour before the MCH administration. The rats were successivelyfed with high fat diet, and their feed intake during the two hoursfollowing the MCH administration was measured.

FIG. 1 shows the feed intake by the high fat diet satiated rats, towhich the compound of the present invention had been orally administeredand an hour thereafter MCH had been administered intraventricularly,during the two hours following said MCH administration, i.e., shows therats' feed intake (g) per the two hours, where 1) said Example 3compound was not administered, 2) Example 3 compound was administered ata rate of 10 mg/kg, and 3) Example 3 compound was administered at a rateof 30 mg/kg.

As demonstrated on FIG. 1, the compound of the present inventiondose-dependently inhibited increase in the amount of feed intake inducedby the MCH which was administered to the rats' third ventricle. In thistest, the feed intake in the case where MCH and artificial liquorcerebrospinalis (aCSF) alone was administered in place of the compoundof the present invention was used as the reference.

INDUSTRIAL UTILIZABLITY

The compounds of the present invention exhibit MCH-1R antagonisticaction and are useful as preventing or treating agents of metabolicdisorders represented by obesity, diabetes, hormone disorder,hyperlipidemia, gout, fatty liver, hepatitis and cirrhosis;cardiovascular disorders, represented by stenocardia, acute orcongestive heart failure, myocardial infarction, coronaryatherosclerosis, hypertension, renal diseases and electrolyteabnormality; central nervous system or peripheral nervous systemdisorders represented by bulimia, emotional disturbance, depression,anxiety, epilepsy, delirium, dementia, schizophrenia, attention-deficithyperactivity disorder, memory impairment, sleep disorders, cognitivefailure, dyskinesia, paresthesias, smell disorders, morphine tolerance,drug dependence and alcoholism; reproductive disorders represented byinfertility, preterm labor and sexual dysfunction; digestive disorders;respiratory disorders; cancer or pigmentation.

1. A compound of general formula [I]:

wherein: R¹ and R² are each independently selected from the groupconsisting of: (1) optionally hydroxyl- or halogen-substituted loweralkyl, (2) optionally R⁹-substituted 3 to 6-membered cycloalkyl, and (3)optionally R⁹-substituted 4 to 6-membered heterocycloalkyl, or (4) R¹and R² together form a 4 to 11-membered crosslinking, non-crosslinkingor spiro ring aliphatic nitrogen-containing heterocycle, with thenitrogen atom to which they bind, one or two optional hydrogen atoms inthe aliphatic nitrogen-containing heterocycle being optionallysubstituted with R⁹; R³, R⁴, R⁶ and R⁷ are each independently selectedfrom the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen,and (4) optionally halogen-substituted lower alkyl; R⁵ stands for: (1)hydrogen, or (2) optionally halogen-substituted lower alkyl; each R⁸ isindependently selected from the group consisting of: (1) halogen, (2)lower alkyl, and (3) lower alkyloxy; R⁹ is selected from the groupconsisting of hydroxyl, amino, mono-lower alkylamino, di-loweralkylamino, optionally hydroxyl- or halogen-substituted lower alkyl,(lower alkyloxycarbonyl)amino, lower alkyloxycarbonyl-(loweralkyl)amino, lower alkylcarbonylamino, lower alkylcarbonyl(loweralkyl)amino, mono-lower alkylcarbamoyl-(lower alkyl)amino, di-loweralkylcarbamoyl(lower alkyl)amino, lower alkylsulfonylamino, loweralkylsulfonyl(lower alkyl)amino, oxo and 2-oxopyrrolidinyl; and n is 0,1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein: R¹ is lower alkyl, and R² isselected from the group consisting of optionally hydroxyl-substitutedlower alkyl, tetrahydrofuranyl and optionally R⁹-substitutedpyrrolidinyl, or a pharmaceutically acceptable salt thereof.
 3. Thecompound according to claim 1, wherein: the 4 to 11-memberedcrosslinking, non-crosslinking or spiro ring aliphaticnitrogen-containing heterocycle formed by R¹ and R² together with thenitrogen atom to which they bind is represented by a formula (A):

wherein R^(a) is R⁹ or two R^(a)s together form —(CH₂)x-(NH)—(CH₂)y-,hydrogen in the substituent group may optionally be substituted withlower alkyl, lower alkylcarbonyl or oxo, x and y are each independentlyselected from 0, 1, 2, 3 or 4, provided that 3≦x+y≦4, and m is selectedfrom 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 3, wherein: R^(a) is selected from the groupconsisting of lower alkylcarbonyl(lower alkyl)amino, loweralkylsulfonyl(lower alkyl)amino, lower alkyloxycarbonyl(loweralkyl)amino, and di-lower alkylcarbamoyl(lower alkyl)amino, and m=1; ora pharmaceutically acceptable salt thereof.
 5. The compound according toclaim 3, wherein: m=2, and the two R^(a)s together form a group selectedfrom the group consisting of:

wherein: R¹⁰ is selected from lower alkyl and lower alkylcarbonyl; or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 3, wherein: the aliphatic nitrogen-containing heterocyclerepresented by the formula (A) is selected from the group consisting of:1-methyl-2-oxo-1,7-diazaspiro[4.4]nonan-7-yl,7-methyl-8-oxo-2,7-diazaspiro[4.4]nonan-2-yl,3-[acetyl(methyl)amino]pyrrolidin-1-yl,3-[propionyl(methyl)amino]pyrrolidin-1-yl,3-[isobutyryl(methyl)-amino]pyrrolidin-1-yl,3-[methanesulfonyl(methyl)amino]pyrrolidin-1-yl,3-[methoxycarbonyl(methyl) amino]pyrrolidin-1-yl,3-{[(dimethylamino)carbonyl](methyl)amino}pyrrolidin-1-yl,6-acetyldecahydro-pyrrolo[3,4-d[azepin-2-yl, and2-oxo]1.3′]bipyrrolidinyl-1′-yl; or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 1, wherein: R⁸ is a fluorineatom or a methoxy group, or a pharmaceutically acceptable salt thereof.8. The compound according to claim 1, wherein: selected from the groupconsisting of: (1)5-(4-fluorophenyl)-N-[2-(1-methyl-2-oxo-1,7-diazaspiro[4,4]nonan-7-yl)-6-quinolinyl]-2-pyrimidinecarboxamide,(2)5-(4-fluorophenyl)-N-[2-(7-methyl-8-oxo-2,7-diazaspiro[4,4]-nonan-2-yl)-6-quinolinyl]-2-pyrimidinecarboxamide,(3)N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide, (4)N-[2-(6-acetyldecahydropyrrolo[3,4-d]azepin-2-yl)-6-quinolinyl]-5-phenyl-2-pyrimidinecarboxamide, (5)N-[2-[(3R)-3-[acetyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide, (6)5-phenyl-N-(2-[(3R)-3-[propionyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide, (7)N-(2-[(3R)-3-[methanesulfonyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide, (8)N-(2-[(3R)-3-[methoxycarbonyl(methyl)amino-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide, (9)N-(2-[(3R)-3-[[(dimethylamino)carbonyl)](methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,(10)N-(2-[isopropyl(methyl)amino]-6-quinolinyl)-5-phenyl-2-pyrimidinecarboxamide,(11)5-(4-fluorophenyl)-N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide,(12)N-(2-[(3R)-3-[acetyl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-5-(4-fluorophenyl)-2-pyrimidinecarboxamide, (13)5-(4-fluorophenyl)-N-(2-[methyl(tetrahydro-3-furanyl)amino]-6-quinolinyl)-2-pyrimidinecarboxamide and (14)5-(3-fluorophenyl)-N-(2-[(3R)-3-[isobutyryl(methyl)amino]-1-pyrrolidinyl]-6-quinolinyl)-2-pyrimidinecarboxamide, or a pharmaceutically acceptable salt thereof.
 9. A methodfor treating obesity in a human subject in need of such treatmentcomprising administering to the human subject of a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 11. A process for preparing the compound of generalformula [I] of claim 1, wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and nhave the same significations as given in claim 1, which comprises thestep of subjecting a compound of a general formula [II]:

 wherein R¹, R², R³, R⁴ and R⁵ are as defined in claim 1; and a compoundof a general formula [III]

 wherein R⁶, R⁷, R⁸ and n are as defined in claim 1; to an amidationreaction.